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ivane javaxiSvilis saxelobis Tbilisis saxelmwifo universiteti

nana wiklauri

zust da sabunebismetyvelo mecnierebaTa fakulteti

biologiis mimarTuleba

araopioiduri analgetikebiT gamowveuli antinocicefciisa da tolerantobis Seswavla

sadoqtoro programis xelmZRvaneli, biologiis mecnierebaTa doqtori, profesori: sulxan cagareli samecniero xelmZRvaneli, biologiis mecnierebaTa doqtori, profesori: merab cagareli

Tbilisi

2010 weli

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sa r C e v i Sesavali 3 Tavi 1. literaturis mimoxilva 8 Tavi 2. kvlevis meTodebi 21 Tavi 3. Sedegebi da maTi ganxilva 23 3.1. anTebis sawinaaRmdego arasteroiduli wamlebis ganmeorebiTi sistemuri (intraperitoniuli) ineqciebis gavlenis

Seswavla nocicepciasa da tolerantobis ganviTarebaze 23 3.2 araopioiduri tolerantoba axalgazrda da zrdasrul virTagvebSi 33 3.2. amigdalas centralur birTvSi anTebis sawinaaRmdego arasteroiduli wamlebis ganmeorebiTi uni- da bilatera-

luri mikroineqciebiT gamowveuli tolerantoba 51

3.3. amigdalas centralur birTvSi arasteroiduli anTebis sawinaaRmdego wamlebis, voltarenis da klodifenis ganmeorebiTi mikroineqciebiT gamowveuli tolerantobis Seswavla hot plate testiT 53

3.5 periaqueduqtis ruxi nivTierebis ventro-lateralur

ubanSi arasteroiduli anTebis sawinaaRmdego wamlebis ganmeorebiTi mikroineqciis Sedegebi 63

3.6. nakeris didi birTvisa da mogrZo tvinis rostro

ventro-medialuri ubnis monawileoba araopioidur analgeziaSi 69

Tavi 4. gansja 77 daskvnebi 81 literatura 82 Sromebis sia 100

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S e s a v a l i tkivili warmoadgens organizmis sapasuxo reaqcias damazianebeli gamRizianeblebis moqmedebaze. miuxedavad usiamovno gancdisa igi organizmis TavdacviTi sistemis miSvnelovani komponenti daHhomeostaturi reaqciebis mudmivad moqmedi regulatoria (Fields, 1987; Melzack, Wall, 1983; Wllis, 1985).

tkivilze organizmis reaqcia mravalkomponentiania da moicavs sensorul-diskriminaciul, emociur-afeqtur da kognitiur maxasiaTeblebs (Melzack and Casey 1968; Willis 1985; Kenshalo and Douglass 1995; Treede 1999; Абзианидзе, 1990; Tsagareli, 2005). tkivilis Semswavleli saerTaSoriso asociaciis (International Association for the Stady of Pain) ganmartebiT tkivili ganisazRvreba, rogorc “usiamovno SegrZneba da uaryofiTi emociuri gancda, dakavSirebuli qsovilis faqtiur an mosalodnel dazianebasTan” (Bonica, 1990; Merskey, Bogduk, 1994). misi TavdacviTi funqciis miuxedavad, gansazRvrul SemTxvevebSi, mas Semdeg rac is Seasrulebs sainformacio rols, tkivili TviTon SeiZleba gaxdes paTologiuri procesis nawili, zogjer ufro saSiSi, vidre misi gamomwvevi dazianeba. amitom mis Seswavlas da mkurnalobis meTodebis Ziebas udidesi roli ukavia Tanamedrove neirobiologiur mecnierebaSi.

mravalricxovani morfo-fiziologiuri gamokvleviT dadgenilia Tavis tvinis struqturebis rigi, romlebic monawileobs tkivilis formirebasa da endogenur analgeziaSi. organizmSi tkivilis aRqmel, nociceptur sistemasTan erTad arsebobs endogenuri antinocicepturi morfo-funqcionaluri sistema, romelic aregulirebs da akontrolebs tkivilis SegrZnebas. Eendogenuri analgeziuri sistemis antinocicepturi moqmedeba ganisazRvreba endogenuri opioiduri, serotoninerguli da adrenerguli meqanizmebiT (Fields et al., 2006; Treede, Apkarian, 2009).

opioidebis roli tkivilis mkurnalobaSi kacobriobisTvis didi xania cnobilia, magram maTi gamoyeneba SezRudulia tolerantobis da wamalze damokidebulebis ganviTarebis gamo (Dickenson, Kieffer, 2006; Hunt, Urch, 2006; Schug, Gandham, 2006). garda opioiduri preparatebisa tkivilis mkurnalobaSi farTod gamoiyeneba araopioiduri, arasteroiduli anTebis sawinaaRmdego wamlebi (asasw). bolo wlebis kvlevebiT nanaxia, rom es preparatebi xangrZlivad moxmarebis SemTxvevaSi iwveven opioidebis msgavs efeqts, tolerantobas (Vanegas, Tortorici, 2002).

araopioiduri tkivilgamayuCebeli wamlebis analgeziuri efeqtebi gamowveulia maTi moqmedebiT centraluri nervuli sistemis (cns) struqturebze da periferiul qsovilebze. am ukanasknelze maTi moqmedeba gacilebiT ukeT aris Seswavlili, vidre cns-ze. cnobilia rom, araopioiduri analgetikebi antinocicepcias iwveven adamianis organizmis sam ZiriTad nawilze moqmedebis gziT, kerZod, anTebis mqone periferiul qsovilebze, zurgis tvinsa da Tavis tvinis Reroze. savaraudod miCneulia, rom tvinis Reros doneze araopioidebi Tavis tkivilgamayuCebel moqmedebas axorcieleben periaqueduktis (wyalsacavis) ruxi (par) nivTierebis gaaqtivebiT. am ukanasknels ganixilaven, rogorc daRmaval, tkivilis makontrolebel sistemas, romelic akavebs tkivilze aRmocenebul signalebs zurgis tvinis ukana rqebis doneze, (Fields et al., 2006; Melzac, Wall, 1983; Heinricher, Ingram, 2009; Keay, Bandler, 2009; Ren, Dubner, 2009).

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erTis mxriv, araopioiduri, kerZod, asasw maTi zurgis tvinze zemoqmedebisas, akaveben tkivilis mgrZnobiare, nociceptur neironebs da amcireben nociceptur pasuxebs araanesTezirebul cxovelebsa da simsivniT daavadebul pacientebSi (Vanegas, Shaible, 2001). meores mxriv, Cveni da sxva kolegebis uaxlesi gamokvlevebi uCveneben, rom iseTi asasw, rogorebicaa ketorolaki, metamizoli (analgini), lizin-acetilsalicilati (lasa) da qsefokami, sistemuri Seyvanis pirobebSi, aaqtiveben tkivilis daRmaval makotrolebel sistemas da akaveben zurgis tvinis nociceptur refleqsebs (Pernia-Andrade, et al, 2004; Tsagareli, et al, 2005, Tsiklauri et al, 2005, 2006). sainteresoa, rom metamizolis, ketorolakisa da qsefokamis intraperitonealuri (i.p.) ineqciiT gamowveuli daRmavali nococepturi Sekaveba xorcieldeba endogenuri opioiderguli wris CarTviT, radganac es ukanaskneli iblokeba naloqsonis (opiaturi receptorebis blokatori) sistemuri SeyvaniT (Tsiklauri, Tsagareli, 2005, 2006; Tsiklauri et al, 2005; 2006). metamizolis, ketorolakisa da qsefokamis ganmeorebiT i.p. ineqciebs mivyavarT antinocicepturi efeqturobis gradualur Semcirebamde, rac gamoixateba tolerantobaSi maT mimarT da kros-tolerantobaSi morfinis i.p. ineqciis mimarT (Tsagareli, et al, 2005; Tsiklauri et al, 2006; Tsiklauri, Tsagareli, 2006). amas, garda naloqsonis sistemuri SeyvaniT aRiniSneba wamlis moxsnis sindromi (Tortorici, Vanegas, 2000). aRniSnuli monacemebi sruliad axlebulad ayeneben sakiTxs asasw-is mier gamowveuli tolerantobis ganviTarebis Sesaxeb, radganac es ukanaskneli fenomeni gamoiwveva opioiduri, anu morfinisa da misi msgavsi preparatebiT. savaraudod, asasw-iT gamowveuli tolerantoba dakavSirebuli unda iyos endogenur tkivilgamayuCebel (antinociceptur) opioidur sistemasTan.

amrigad, asasw-is moqmedebis meqanizmebis Seswavla uaRresad aqtualuri da mniSvnelovania samedicino praqtikisTvis, imdenad ramdenadac araopioidebis mimarT tolerantobis ganviTareba, wamlis moxnis sindromTan erTad SeiZleba Seicavdes garkveul, potenciur risks klinikuri praqtikisTvis da iwvevdes seriozul samedicino da socialur garTulebebs. amrigad, warmodgenili naSromi Zalian mniSvnelovania, rogorc fundamenturi fiziologiuri mecnierebisTvis, ise klinikuri medicinisTvis. kvlevis mizani da amocanebi: warmodgenili naSromis ZiriTad mizans Seadgenda virTagvebSi araopoiodebiT gamowveuli tolerantobis centraluri (Tavis tvinis) meqanizmebis Seswavla qronikuli eqsperimentis pirobebSi. kerZod, dadgena, iwvevs Tu ara araopioiduri wamlebis (metamizoli, ketorolaki, qsefokami, klodifeni) sistemuri da mikroineqciebi Tavis tvinis garkveul struqturebSi xuTi uwyveti DdRis ganmavlobaSi tolerantobis ganviTarebas da kros-tolerantobas morfinis mimarT eqsperimentul da sakontrolo cxovelTa jgufebSi da am movlenis kavSirs Tavis tvinis endogenur antinociceptur sistemasTan.

aRniSnulidan gamomdinare, Cvens mier dasmul iqna Semdegi konkretuli amocanebi:

• qronikuli eqsperimentis pirobebSi asasw-is ganmeorebiTi sistemuri, (intraperitoniuli) ineqciebis gavlenis Seswavla nocicepciaze da tolerantobis ganviTarebaze.

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• virTagvebis or asakobriv jgufSi (axalgazrda da zrdasruli) nocicefciisa da tolerantobis ganviTarebis dinamikis Seswavla asasw-is ganmeorebiTi intraperitonialuri ineqciebis Sedegad.

• amigdalas centralur birTvSi asasw-is ganmeorebiTi uni- da bilateraluri mikroineqciebis gavlenis Seswavla nocicepciaze da tolerantobis ganviTarebaze

• periaqueduqtis rux nivTierebaSi (par) asasw-is ganmeorebiTi mikroineqciebis gavlenis Seswavla nocicepciaze da tolerantobis ganviTarebaze.

• nakeris did birTvSi asasw ganmeorebiTi mikroineqciebis gavlenis Seswavla nocicepciaze da tolerantobis ganviTarebaze.

• mogrZo tvinis rostralur ventro-medialur ubanSi asasw-is ganmeorebiTi mikroineqciebis gavlenis Seswavla nocicepciaze da tolerantobis ganviTarebaze.

naSromis mecnieruli siaxle: pirvelad aris dadgenili, rom araopioidebis, asasw-is ganmeorebiTi Seyvana msgavsia opioidebis, magaliTad morfinis ganmeorebiTi Seyvanisa. araopioiduri tkivilgamayuCebeli wamlebis analgeziuri efeqtebi nawilobriv gamowveulia centraluri nervuli sistemis (cns) struqturebze maTi moqmedebiT.

pirvelad aris dadgenili, rom asasw, rogorebicaa ketorolaki, metamizoli (analgini) da qsefokami, sistemuri Seyvanis pirobebSi, aaqtiveben tkivilis daRmaval makotrolebel sistemas da akaveben zurgis tvinis nociceptur refleqsebs.

pirvelad aris dadgenili, rom metamizolisa da ketorolakis intraperitonealuri (i.p.) ineqciiT gamowveuli Sekaveba xorcieldeba daRmavali endogenuri opioiderguli wris CarTviT, radganac es efeqti iblokeba naloqsonis sistemuri SeyvaniT.

pirvelad aris dadgenili, rom metamizolis, ketorolakisa da qsefokamis ganmeorebiT i.p. ineqciebs mivyavarT antinocicepturi Zalis progresul Semcirebamde, rac gamoixateba tolerantobaSi maT mimarT da kros-tolerantobaSi morfinis i.p. ineqciis mimarT. naloqsonis sistemuri SeyvaniT aRiniSneba wamlis moxsnis sindromi.

pirvelad aris dadgenili, rom asasw-iT gamowveuli tolerantoba dakavSirebuli unda iyos endogenur tkivilgamayuCebel (antinociceptur) opioidur sistemasTan. amdenad, asasw-is moqmedebis Seswavla uaRresad aqtualuri da mniSvnelovania samedicino praqtikisTvis.

pirvelad aris dadgenili, rom par nivTierebaSi araopioiduri analgetikebis mikroineqcia sinergistulad unda moqmedebdes endogenur opioidebTan, da unda iwvevdes ciklo-oqsigenazebis blokirebas.

pirvelad aris dadgenili, rom par nivTierebaSi mikroinicirebuli metamizolis efeqtebi mcirdeba imave ubanSi naloqsonis mikroineqciiT, rac dakavSirebuli unda iyos adgilobriv (lokalur) endogenur opioidebTan.

pirvelad aris dadgenili, rom nuSisebri sxeulis (amigdalas) centraluri birTvi (acb), nakeris didi birTvi (ndb) da mogrZo tvinis

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rostraluri ventro-medialuri (rvm) ubani monawileoben tolerantobis ganviTarebaSi.

pirvelad aris dadgenili, rom naloqsonis - morfinis receptorebis blokatoris inieqcia amcirebs asasw-is efeqtebs, rac imaze miuTiTebs, rom araopioidebis centralur antinociceptur moqmedebaSi CarTuli unda iyos endogenuri opioiduri sistema.

kvlevis Teoriuli da praqtikuli mniSvneloba: pirvelad iqna gamocdili asasw-is farTo speqtri (analgini, ketorolaki, qsefokami, diklofenaki) maTi tolerantobis efeqtebisa da meqanizmebis Sesaswavlad. miRebulma Sedegebma, pirvelad mogvca SesaZlebloba dagvedgina mWidro kavSiri endogenur antinociceptur opioidergul sistemasa da ZiriTad, medicinaSi farTod gamoyenebul araopioidur analgetikebs Soris. am faqtma gaafarTova Cveni codna araopioiduri asasw-is gamoyenebis SesaZleblobebis Sesaxeb ambulatoriul da klinikur praqtikaSi. Cveni da sxva avtorTa mecnieruli Sedegebis Tanaxmad araopioidur tolerantobas gaaCnia opioiduri tolerantobis msgavsi buneba. naSromis aprobacia disertaciis masalebi warmodgenili iyo: fiziologiuri sazogadoebis saerTaSoriso workshop-ze (kievi 2006); evropis neiromecnierebis V (vena, avstria, 2006) da VI (Jeneva, Sveicaria, 2008) forumebze; evropis tkivilis V (stambuli, TurqeTi, 2006) da VI (lisaboni, portugalia, 2009) kongresebze; aSS-is neiromecnierebis sazogadoebis wliuri kongresebze (vaSingtoni, 2008; Cikago, 2009); evropis tvinisa da qcevis sazogadoebis 41-e wliuri konferenciaze (rodosi, saberZneTi, 2009); fiziologiur mecnierebaTa 36-e saerTaSoriso kongresze (kioto, iaponia, 2009); rig adgilobriv konferenciebze; agreTve beritaSvilis sax. fiziologiis institutis neirofiziologiis ganyofilebis gafarToebul sxdomaze (Tbilisi, 2007 w. 18

seqtemberi, oqmi № 1).

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Ppublikaciebi: gamokvlevis Sedegebi gamoqveynebulia 15 statiis da 17 Tezisis saxiT. disertaciis struqtura da moculoba: sadisertacio naSromi moicavs kompiuterze nabeWd 99 gverds da ilustrirebulia 41 suraTiT. naSromi Sedgeba Semdegi Tavebisagan: Sesavali, literaturis mimoxilva, kvlevis masala da meTodebi, miRebuli Sedegebi da maTi ganxilva, daskvnebi da literaturis sia. literaturis sia moicavs 237 dasaxelebas.

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Tavi I. literaturis mimoxilva tkivili warmoadgens integralur fenomens, romlis formirebasa da

modulaciaSi monawileobs nervuli struqturebis rTuli kompleqsi. cxovelebisa da adamianis organizmSi tkivili gamoiwveva sxvadasxva gamRizianebeli faqtoriT. tkivilis SegrZnebas organizmisTvis dacviTi mniSvneloba aqvs da sxva sensoruli SegrZnebebisagan gansxvavebiT is nakleb informacias gvawvdis gare samyaros Sesaxeb. tkivili aris ara marto sensoruli SegrZneba, aramed emociuri gancdac. rogorc avRniSneT SesavalSi, tkivilis Semswavleli saerTaSoriso asociaciis (International Association for the Stady of Pain) ganmartebiT tkivili ganisazRvreba, rogorc “usiamovno SegrZneba da uaryofiTi emociuri gancda, dakavSirebuli qsovilis faqtiur an mosalodnel dazianebasTan”M(Merskey and Bogduk 1994). Tumca es ganmartebac ver aRwers tkivils srulyofilad, radgan is warmoadgens rTul kompleqsur fenomens, romelic moicavs sensorul, emociur da kognitiur komponentebs. amdenad, tkivili warmoadgens subieqtur, cvalebad SegrZnebas da organizmis integralur funqcias, romelic axdens sxvadasxva funqciuri sistemis mobilizacias mavne faqtorebis zemoqmedebis Tavidan asacileblad. sxvadasxva adamianis reaqcia tkivilze gansxvavebulia, iseve rogorc erTi da igive adamianis reaqcia gansxvavdeba sxvadasxva pirobebSi.

sxva sensoruli SegrZnebebis msgavsad, tkivilis SegrZnebas aRiqvamen specializirebuli receptorebi, nociceptorebi, romlebic amoicnoben, gardaqmnian da gadascemen signalebs cns-Si. aRmoCenilia meqano-, Termo- da meqano+Termo mgrZnobiare receptorebi. am ukanasknels polimodalur receptorebs uwodeben da maTi raodenoba danarCen or tipze gacilebiT metia (Treede at al. 1999; Mense, 2009; Meyer et al., 2006). N nocicepturi stimulis gadacema ori saxis nervuli boWkoebiT xdeba _ wvrili mielinizirebuli A-delta da umielino C boWkoebiT. gavrcelebis siCqare pirveli saxis boWkoebSi Seadgens 2,5-dan 20 m/wm-mde, xolo meoreSi 2,5 m/wm-dan qveviT. tkivilis SegrZneba samneironiani gziT tardeba, romelic nociceptur stimuls periferiidan Tavis tvinis qerqs gadascems.

nocicepturi informaciis gamtari A delta da C Aaqsonebi bolovdebian upiratesad dorsaluri rqis zedapirul I da II SreSi. nocicepturi aferentebi gamoanTavisufleben amagznebel neirotransmiter glutamats, agreTve amagznebel peptidebs, kerZod, substancia P-s da kalcitoninis genTan dakavSirebul peptids (Todd 2002; Willis, Coggeshall 2003; Hunt 2004; Ribeiro-da-Silva, De Konink, 2009). N

zurgis tvinis ukana rqebis neironuli wreebis gziT nocicepturi informaciis mxolod amavali mimarTulebiT gatareba ki ar xdeba, aramed adgili aqvs sensoruli procesebis integracias. zurgis tvinis ukana rqebSi mosuli sensoruli informacia ganicdis rTul gadamuSavebas, ris Sedegadac mosuli impulsaciis nawili kavdeba da mxolod nawili gadaecema supraspinalur doneze (Todd, Koerber, 2006; Light, Lee, 2009).

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nocicepturi informaciis gamtari gzebi spinoTalamuri traqtiT dorsaluri rqis I Sridan gamomavali boWkoebi, romlebic ZiriTadad nocicepturi specifikisaa, bolovdebian Talamusis ventro-postero-medialur da ventro-postero-lateralur birTvSi (Willis et al. 2002 ; Willis 2004, Dostrovsky, Craig, 2006). es birTvebi identificirebulia, rogorc zurgis tvinis ukana rqis pirveli Sridan mtkivneuli stimulis Sesaxeb “specifikuri” informaciisa da temperaturuli informaciis mimRebi birTvebi. Talamusis es regionebi proeqciebs iZleva insularuli qerqSi (Craig 2004; Gauriau and Bernard 2004; Lima, 2009; Dostrovsky, Craig, 2009).

zurgis tvinis ukana rqis neironebi pirdapir proeqciebs iZlevian tvinis ReroSi. tkivils xSirad Tan axlavs motivaciur emociuri reaqcia, rac gamovlindeba tanjvis, SfoTvis, yuradRebis gaZlierebis, guliscemis gaxSirebis, wnevis awevis, avtonomiuri, endokrinuli da imunuri sistemebis moqmedebis cvlilebis saxiT (Janig, Levine, 2006; Keay, Bundler, 2009; Rittner, et al., 2009). nervuli struqturebi, romlebic aRZravs amgvar cvlilebebs, albaT paralelurad iRebs informacias nocicepturi Sesavlidan. zogierT amaval gzas xelsayreli pozicia ukavia am rolis Sesasruleblad. es is gzebia, romlebic gaivlis solitaruli traqtis birTvebs, mogrZo tvinis rostro-ventralur ubans, dorsolateraluri xidis parabraqialur birTvs, centralur rux nivTierebas, hipoTalamuss da amigdalas (Willis 2004; Dostrovsky, Craig, 2006; Lima, 2009).

Ddadgenilia agreTve pirdapiri proeqciebi zurgis tvinis ruxi nivTierebidan nakeris did birTvze, aseve aRwerilia kavSirebi ventromedialur medulasa da xidis kateqolaminergul neironebs Soris (Clark, Proudfit, 1991). amavali tkivil-gamtari gzebi proeqciebs iZleva centralur rux nivTierebaSi da Sua tvinis retikularul formaciaSi (Basbaum, Fields 1984; Chaouch et al.1983; Zhang et al.1990; Craing, 1996 ; Dostrovsky, Craig, 2006; Lima, 2009). tkivilis daRmavali modulacia tkivili, rogorc sensoruli procesi, aRiqmeba cns-is mier, magram amave dros is kontroldeba anu modulirdeba mis mierve. Ees aris tkivilis modulatoruli endogenuri sistema da masSi tvinis Reros daRmaval gzebs fundamenturi mniSvneloba gaaCniaT (Fields et al, 2005; Millan 2002; Ren, Dubner, 2009; Heinricher et al, 2009; Heinricher, Ingram, 2009).

am meqanizmis arsebobis Sesaxeb miuTiTebda mravali avtori, magram pirveli damamtkicebeli monacemebi miRebuli iyo gasuli saukunis samociani wlebis dasasruls, rodesac naCvenebi iqna, rom Sua tvinis wyalsacavis (periaqueduqti) mimdebare ubnis eleqtruli stimulacia iwvevs analgezias (Reinolds 1969). es aRmoCena, dadasturda sxva avtorebis mierac (Mayer, Lieberskind, 1974; Simpson, et al., 2006).

cns-Si arsebobs mravali ubani da gza, romlebic CarTulni arian tkivilis daRmaval modulaciaSi. dReisaTvis yvelaze ukeT Seswavlilia, nervuli gzebis wre, Sua tvinis periaqueduqtis ruxi nivTiereba (par) _ mogrZo tvinis rostraluri ventromedialuri medula (rvm) _ zurgis tvinis ukana rqebi. Tavis mxriv, rvm moicavs nakeris did birTvsa da mimdebare retikulur formacias. tkivilis kontrolis meore mniSvnelovani ubani mimdinareobs dorsolateraluri ponto-mezencefaluri tegmentumidan (dlpt), romelic moicavs solisebr birTvsa da cisfer laqas. mogrZo tvinis

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kaudalur ventro-lateralur nawilSi aRsaniSnavia lateraluri retikuluri birTvi, dorsaluri retikuluri birTvi da solitaruli traqtis birTvi. hipoTalamusi da nuSisebri xveuli (amigdala) aseve monawileobs tkivilis daRmaval modulaciaSi (Millan 2002, Fields et al, 2006, Baccei, Fitzgerald, 2006; Ren Dubner 2009; Heinricher, Ingram, 2009) par-rvm modulatoruli wre mniSvnelovania ara marto eleqtruli, aramed opioiduri analgeziisTvisac, es struqturebi aris opioiduri analgetikebis moqmedebis centraluri substrati da CarTulia opioiduri analgeziis da opioidebisadmi fiziologiuri damokidebulebis sindromis formirebaSi (Dickenson, Kieffer, 2006; Morgan et al., 2009). par-i lokalizebulia Sua tvinSi, wyalsadenis garSemo da mniSvnelovan rols asrulebs tkivilis daRmaval modulaciaSiMda TavdacviT qcevaSi. rvm-i moicavs Sua xazis nakeris birTvebs da mis axlomdebare retikulur formacias, romelic mdebareobs retikuluri gigantocelularuli birTvis ventralurad. rvm-is eleqtruli stimulacia an masSi amagznebeli aminomJavebis mikroineqcia iwvevs analgezias da zurgis tvinis dorsaluri rqis neironebis pasuxebis inhibirebas mtkivneul stimulaciaze (Feilds 1991, Morgan et al 2005; Heinricher, Ingram, 2009; Ren, Dubner, 2009).

morfinis an sxva µ-opioiduri agonistebis pirdapiri aplikacia orive ubanSi iwvevs morfinis sistemuri SeyvaniT gamowveuli analgeziis msgavs moqmedebas (Heinricher, Ingram 2009; Fields et al, 2006 ; Morgan et al 2008). Ees sistema aqtivdeba mwvave stresis (tkivilis) dros da opioiduri analgetikebi akaveben tkivilis aRqmas, nocicefcias zurgis tvinis doneze. par-i Seicavs

sami tipis µ, δ, da κ-opioidur receptorebs da mdidaria endogenuri opioidebiT, rogorebicaa enkafalini, endorfini, dinorfini (Dickenson, Kieffer, 2006; Dray. 2009; Zubieta, 2009).

par-Si morfinis agonistebis pirdapiri aplikacia iwvevs Zlier antinocicefcias, romelic xorcieldeba rvm-Si proecirebuli neironebiT. imunoqimiuri da konfokaluri mikroskopis saSualebiT nanaxia par-is neironuli proeqciebi zurgis tvinSi rvm-is gavliT. am retikulo-spinaluri neironebis 2/3 gaemergulia (Morgan, 2008).

rvm-is neironebis nawili akavebs tkivils, nawili ki amsubuqebs mis gadacemas. nocicepturi refleqsebis dros rvm-is ON-neironebis aqtivoba izrdeba da maTi aqtivobis gazrda iwvevs nocicefciis gaadvilebas (Bederson et al. 1990; Budai et al 2007; Gardell et al.2003; Goncalves et al.2007; Osborne et al.1996; Vera-Portocarrero et al 2006), OFF-neironebi nocicepturi refleqsebis dros avlenen pauzas aqtivobaSi anu ‘’Cumad arian’’, xolo morfinuli an sxva saxiT gamowveuli analgeziis dros izrdeba maTi aqtivoba (Barbaro et al. 1989; Fang et al.1989; Heinricher and Drasner 1991; Heinricher and Tortorici 1994;. Morgan and Fields 1993;.Morgan et al 1992; Osborne et al 1996; Tortorici and Morgan 2002; Tortorici and Vanegas 1994)

par-Si morfinis mikroineqciebi antinocicefcias iwveven gaemerguli neironebis SekavebiT, rac Tavis mxriv iwvevs, rvm-Si maTi samizne neironebis ganSekavebas (Vaughan et al.,1997; Vera-Portocarrero et al., 2006). par-is gamosavlis neironebi antinocicefciaSi monawileoben rogorc ON- neironebis SekavebiT, ise OFF-neironebis agznebiT (Pinault, 1996), an erTdroulad orive gziT (Tortorici, Morgan, 2002). rvm-Si amagznebeli mediatoria glutamati, xolo Semakavebeli gaem-i (Heinricher and McGaraughty, 1998, Heinricher and Tortorici 1994;).

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eleqtrofiziologiuri meTodebiT nanaxia, rom par-dan rvm-is ON-neironebzeNproecirebuli neironebi Seicaven gaem-s da analgezia xorcieldeba maTi SekavebiT, xolo OFF-neironebze proecirebadi neironebi Seicaven glutamats, da es neironebi morfinuli analgeziis dros avlenen gazrdil aqtivobas (Cheng et al., 1986; Kincaid et al,. 2006; Kalyuzhny and Wessendorf, 1998; Reichling and Basbaum, 1990). par-dan rvm-Si proecirebad gaemergul neironebze aRmoCenilia µ- receptorebi da morfinis Seyvana iwvevs am neironebis Sekavebas (Commons et al., 2000; Wang and Wessendorf, 2002).

par-dan rvm-is gavliT, zurgis tvinis ukana rqis neironebze gavlena Sewavlilia anterograduli P(par-dan) da retrograduli (zurgis tvinis cervikaluri nawilidan) gzebis aRmoCeniT gaem-is sintetikuri enzimis GAD-67-is gamoyenebiT imunoqimiur cdebSi (Morgan, 2008). am kvlevebiT nanaxia, rom par-dan anterogradulad moniSnuli neironebi ukavSirdebian rvm-Si retrogradulad moniSnul retikulospinalur neironebs. magram es kavSirebi nanaxia retikulo-spinaluri neironebis mxolod 33 procentSi da rvm-Si markirebuli neironebis mxolod 53 procenti Seicavs GAD-67, anu gaem-ergulia. am cdebiT (Morgan 2008) agreTve aRmoCnda, rom par-is neironebi ukavSirdebian rvm-is samive tipis neironebs, rac kidev erTxel miuTiTebs, rom par-i tkivilis modulacias axdens ori sxvadasxva mimarTulebiT ON-neironebis SekavebiT da OFF-neironebis gaaqtivebiT.

garda gaem-erguli kavSirebisa, nanaxia agreTve aragaem-erguli kavSirebi. miuxedavad pirdapiri proeqciebisa par-dan rvm-is neitralur neironebze, eleqtrofiziologiuri kvlevebiT ar aris nanaxi kavSiri nocicepciis cvlilebasa da neitraluri ujredebis aqtivobas Soris (Cheng at al., 1986). rvm-is neitraluri neironebis nawili markirebulia GAD-67-iT, magram maTi funqcia garkveuli ar aris, maTi naxevari serotoninergulia (Potrebic at al., 1994; Winkler at al., 2006; Yang at al., 2002). nanaxia, rom samive tipis neironebi proecirdebian zurgis tvinSi (Morgan, 2008). gaem-erguli receptorebi nanaxia rvm-is, rogorc serotoninergul ise ara-serotoninergul neironebze (Hama at al.,1997) da serotoninerguli neironebi aseve proecirdebian zurgis tvinSi (Yang et al. 2002).

zurgis tvinSi serotoninerguli neironebis blokirebiT sustdeba rvm-is aqtivaciiT gamowveuli antinocicefcia (Hurley at al., 2003), rac miuTiTebs, rom serotonini uSualod ar monawileobs antinocicefciaSi, magram rogorc Cans SeuZlia nocicefciis modulireba garkveul situaciebSi. P par-rvm interaqtivobis modeli moicavs agreTve amagznebel glutamatergul proeqciebs (Aimone and Gebhart, 1986; Praag and Frenk, 1990; Wiklund et al., 1988) am modelis Tanaxmad opioidebi antinocicefcias iwveven par-Si gaemerguli neironebis SekavebiT, rac iwvevs gamosavlis glutamaterguli neironebis ganSekavebas, romlebic proeqciebs rvm-is OFF- neironebze iZleevian (Vaughan and Christie 1997), xolo maTi gaaqtiveba nocicefcias akavebs zurgis tvinis doneze.

rogorc vxedavT, par-dan rvm-Si aris, rogorc gaem-erguli ise aragaem-erguli Sesavlebi. Ppar-is mraval gaem-ergul neironze, romlebic Sesavlebs rvm_Si iZleva, nanaxia µ-opioiduri receptorebi (Commons at al., 2000; Kalyuzhny at al., 1996), rac naTels hfens morfinis antinociceptur efeqts. rvm-is yvela ON- da OFF-neironi ar proecirdeba zurgis tvinSi (Morgan et al

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2009), rac miuTiTebs, rom am neironebis nawili proecirdeba sxva ubnebSi da sxva meqanizmebSi arian CarTulni. (sur.1)

sur. 1 tvinis Reros tkivilis mamodulirebeli sistemis funqciuri organizacia, daRmavali gzebi Sua tvinis periaqueduqtis ruxi nivTierebidan (par) rostraluri ventromedialuri medulas (rvm) gavliT zurgis tvinis ukana rqaSi. Ees sistema tkivilis kontrols axorcielebs ori gziT, rvm-is tkivilis gamadvilebeli on- neironebis SekavebiT da tkivilis Semakavebeli off-neironebis agznebiT. Ppar-i prefrontalur qerqs, amigdalas da hipoTa- lamusTan erTad warmoadgens nocicefciaze emociuri da kognitiuri cvlilebebis anatomiur substrats(Heinricher, Ingram, 2009).

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tolerantoba opiatebi warmoadgens yvelaze efeqtur tkivilgamayuCebel saSualebas,M magram maTi Semdgomi ganmeorebiTi inieqciebi iwveven tolerantobis ganviTarebas, anu mcirdeba wamlis farmakologiuri efeqti da sasurveli analgeziuri efeqtis misaRebad saWiroa dozis gazrda. tolerantobis ganviTarebis mravali meqanizmia mowodebuli, magram jerjerobiT ucnobia is ujreduli cvlilebebi, rac SeiZleba safuZvlad edos mas. amitom Zalian mniSvnelovania im struqturebis gamovlena, romlebic monawileoben am fenomenis ganviTarebaSi.

opiatebi antinonocicepcias iwveven sul mcire im mamodulirebeli gzebis gaaqtivebiT, romlebic moicaven par-rvm sistemas (Basbaum and Fields, 1984, Fields et al.,1991,). am struqturebSi morfinis mikroineqcia iwvevs antinocicefcias ( Jacquet and Lajtha, 1976; Jensen and Yaksh, 1986; Morgan et al. 1998; Yaksh et al., 1976). par-Si morfinis da sxva opioiduri agonistebis pirdapiri aplikacia iwvevs Zlier analgezias, romelic xorcieldeba rvm-ze proecirebuli neironebiT (Tortorici and Morgan, 2002; Morgan, 2005). am wamlebis ganmeorebiTi mikroineqciebisas par_Si viTardeba mkveTrad gamoxatuli tolerantoba (Jacquet and Lajtha, 1976; Lewis and Gebhart, 1977; Siuciak and Advokat, 1987; Tortorici et al., 1999, Morgan et al., 2005). morfinis ganmeorebiTi sistemuri Seyvana iwvevs rvm-sa da mis axlomdebare ubnebSi neironuli aqtivobis cvlilebas (Bederson at al, 1990; Li and Wang, 2001). rvm-is inaqtivacia asustebs morfinis sistemuri SeyvaniT gamowveul analgezias (Oliveras et al., 1978) da ganmeorebiTi sistemuri SeyvaniT ganviTarebul tolerantobas (Vanderah et al., 2001).

morfinuli tolerantoba viTardeba rvm-Si morfinis ganmeorebiTi mikroineqciebis Semdegac, magram morfinis mikroineqciiT gamowveuli antinocicefcia bevrad Zlieria par-Si, vidre rvm-Si (Morgan and Whitney, 2000; Tortorici and Morgan, 2002) da rvm-is neironebi bevrad rezistentulebi arian tolerantobis mimarT, vidre par-is neironebi. erTi da igive pirobebSi tolerantobis ganviTarebis xarisxi bevrad Zlieria par-Si, vidre rvm-Si (Morgan, 2005; Lane, 2005). amrigad, miuxedavad didi rolisa, romelsac rvm asrulebs, morfinuli analgeziisa da tolerantobis mTavar ubans mainc par-i warmoadgens, amitom es struqtura ganixileba, rogorc opioiduri tolerantobisa da damokidebulebis ‘’ZiriTadi’’ ubani.

par-is gamosavlis neironebis ganmeorebiTi aqtivaciisas ar viTardeba tolerantoba (Morgan et al. 2003), rac miuTiTebs, rom tolerantobis meqanizmi lokalizebuli unda iyos im neironebze, romlebic funqciurad win uswreben gamosavlis neironebs. savaraudod es aris opioid-mgrZnobiare gaem-erguli neironebi, romlebic akaveben gamosavlis neironebs da am varauds adasturebs eqsperimentebi sadac nanaxia, rom Mmorfinis ganmeorebiTi sistemuri SeyvaniT gamowveuli tolerantobis dros, par-is opioid-sensitiur gaemergul neironebSi icvleba neironuli pasuxebi (Chieng and Christie., 1996; Ingram, 1998)

miuxedavad imisa, rom mravali kvlevebiT naCvenebia rvm-is neironebis roli morfiniT gamowveul tolerantobis ganviTarebaSi, masSi mimdinare neironuli cvlilebebi savaraudod meoradia da Sedegia sxva neironul struqturebSi tolerantobis dros mimdinare cvlilebebisa. kerZod, ventrolateralur par-Si da rogorc zemoT avRniSneT, par-Si morfinis

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agonistebis ganmeorebiTi mikroineqcia virTagvebSi iwvevs bevrad Zlier da swrafad ganviTarebad tolerantobas vidre rvm-Si, amitomac ganixileba par-i, rogorc opioiduri tolerantobisa da damokidebulebis struqtura. (Morgan et al., 2005 ; Behbehani, 1981; Tortorici et al., 2001).

Zalian sainteresoa μ-opioiduri receptorebis gansxvavebuli efeqturobis mqone agonistebis moqmedeba zurgis tvinsa da par-Si. am wamlebis, rogorc sistemurma, ise zurgis tvinSi intraTekalurma ineqciebma aCvena, rom nakleb efeqturi opioidebi, rogoricaa morfini iwvevs bevrad Zlierad gamoxatul tolerantobas, vidre maRal efeqturi opioidebi, rogoricaa, fentanili, sufanetili, etorfini, DAMGO – (D-Ala2, NmePhe4, Gly-o15) (Duttaroy and Yoburn, 1997; Paronis and Holtzman, 1992; Walker and Young, 2001). Uufro metic, DAMGO-s da morfinis erToblivi intraTekaluri Seyvana blokavs morfinul tolerantobas (He et al., 2002), rac miuTiTebs, rom DAMGO akavebs morfinuli tolerantobis ganviTarebas zurgis tvinis doneze. ventrolateraluri par-i warmoadgens morfinuli analgeziis da tolerantobis ganviTarebis mTavar ubans (Jacquet and Lajtha, 1976; Lane at al., 2005; Morgan et al., 2006, Tortorici et al., 1999). DAMGO-s mikroineqcia par-Si iwvevs antinocicefcias, xolo misi ganmeorebiTi Seyvana tolerantobas da kros-tolerantobas morfinis mimarT. Mmorfinis da DAMGO-s erToblivi mikroineqcia ki iwvevs bevrad Zlier da swrafad ganviTarebad tolerantobas vidre isini iwveven cal-calke (Meyer et al., 2007). es monacemebi gviCvenebs, rom par-Si DAMGO da morfini erTi da igive meqanizmebiT axorcieleben Tavis moqmedebas da sawinaaRmdegod amisa sistemuri da zurgis tvinSi Seyvanili dabal-efeqturi (morfinis) da Zlier-efeqturi (DAMGO) opioidebis gansxvavebuli moqmedeba ki unda miuTiTebdes gansxvavebuli meqanizmebis arsebobaze (He at al., 2002; Roerig et al., 1985; Tseng et al., 1993). Ees monacemebi miuTiTebs, rom cns-is sxvadasxva ubnebSi SeiZleba arsebobdes tolerantobis ganviTarebis sxvadasxva meqanizmebi (Porreca et al., 1987), xolo opioidebis sistemuri Seyvanisas ganviTarebuli tolerantoba aris cns-is sxvadasxva ubnebis sinergistuli moqmedebis Sedegi ( Fairbanks and Wilcox, 1999; Kolesnikov et al, 1996; Rossi et al., 1993).

gansxvavebuli nocicepturi profilis wamlebis supraspinaluri da spinaluri Seyvanis Semdeg ganviTarebuli efeqtebi SeiZleba gamowveuli iyos opioiduri receptorebis gansxvavebuli subtipebis arsebobiT. Mmag. opioiduri antagonisti naloqsonazini ukavSirdeba Mμ-1 da μ-2 receptorebs (Pasternac, 2001). zurgis tvinsa da ventrolateralur par_Si arsebobs μ- receptorebis gansxvavebuli subtipi. kvlevebiT nanaxia, rom zurgis tvinSi antinocicefcia gamoiwveva μ-2 receptoruli kavSirebiT (Pick et al., 1991; Paul et al., 1989), xolo supraspinalur ubnebSi μ-1 (Moskowits and Goodman, 1985; Ling et al., 1989). supraspinalur da spinalur ubnebSi μ-opioiduri receptorebis gansxvavebuli eqspresia naTels xdis Tu ratom mimdinareobs am struqturebSi gansxvavebulad tolerantobis ganviTareba (He at al., 2002; Paul et al., 2007). ventrolateralur par_Si opioiduri receptorebis dablokviT SesaZlebelia sistemuri morfinuli tolerantobis prevencia (Lane et al., 2005). rogorc qceviTi, ise in vitro cdebiT naCvenebia, rom tolerantobis meqanizmi SesaZloa xorcieldebodes opioid-mgrZnobiare gaem-erguli neironebSi mimdinare cvlilebebiT (Chieng and Christie, 1996; Ingram et al., 1998; Morgan et al., 2003) .

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par-is opioiduri receptorebi monawileobas iReben mTeli rig qceviT reaqciebSi – nocicepturi modulacia, kardio-vaskularuli regulacia, Termoleguracia, lokomoturi aqtioba (Cavun at al., 2004; Cavun and Millington, 2001; Keay et.al. 1993; Morgan et al., 1998; Widdowson et al., 1983). δ-opioiduri receptorebis gaaqtivebac iwvevs antinociceptur pasuxebs, magram bevrad sustad vidre µ-opioiduri receptorebisa (Bernal et al. 2007; Ossipov at al., 1995; Rossi at al., 1994).

δ-opioiduri receptorebi xasiaTdebian didi mobilurobiT, morfin- tolerantul virTagvebSi. nanaxia maTi intensiuri gadaadgileba citoplazmidan plazmur membranaze, rogorc zurgis tvinSi (Cahill et al., 2001; Morinville, et al., 2003), ise par-Si (Commons et al., 2001). curviTi stresis drosac mkveTrad izrdeba maTi raodenoba par_is neironebis membranaze (Commons, 2003).

In vitro cdebiT nanaxia, rom δ-opioiduri receptorebis (dori) agonistebi ar cvlian gaemerguli neironebis sinapsur gadacemas par_Si (sakontrolo cxovelebi) (Chieng and Christie, 1994; Vaughan and Christie, 1997), maSin roca morfin-tolerantul virTagvebSi akaveben gaem-ergul neironebs (Hack et al., 2005). dor-is gazrdili eqspresia par-Si morfin tolerantul virTagvebSi SesaZloa iyos kompensatoruli meqanizmi µ-receptorebis mier antinocicepturi efeqtis dakargis gamo. delta receptoris agonistis, deltorfin-2-is, intratekalurad Seyvanisas izrdeba, rogorc am receptorebis eqspresia zurgis tvinSi, aseve antinocicefcia (Cahill et al.., 2001). M morfin tolerantul virTagvebSi deltorfin-2-is Seyvana par_Si ar iwvevs antinocicefcias, magram icvleba qceviTi pasuxebi, rac gamoixateba lokomotoruli aqtivobis daqveiTebaSi (Morgan, 2009), es miuTiTebs, rom morfinis qronikuli Seyvanis dros icvleba dor-is receptorebis simkvrive ventrolateralur par-Si,A anu daRmavali modulatoruli sistemis funqcionirebaSi, romelic moicavs par – rvm – zurgis tvinis sistemas. amdenad, δ-opioiduri receptorebic asruleben mniSvnelovan rols μ-receptorebTan erTad (Hurley et al., 1999; Jensen and Yaksh, 1986; Lane, 2005; Thorat and Hammond, 1997). antinocicefcia, gamowveuli δ-opioiduri agonistebis mier aris SedarebiT susti vidre morfiniT gamowveuli (Rossi et al., 1994), magram is faqti, rom morfin tolerantul virTagvebSi deltorfinis Seyvana ar iwvevs antinicicefcias, anu viTardeba krostolerantoba mis mimarT, savaraudod gamowveuli unda iyos imiT, rom morfini blokavs doris gadaadgilebas citoplazmidan plazmur membranaze (Morgan, 2007). rogorc Cans, dor-receptorebi, ventrolateralur par-Si ganviTarebuli morfinuli tolerantobis dros, monawileoben mxolod lokomociur aqtivobaSi da ara antinocicepturi efeqtebis regulaciaSi (Fanselow, 1991; Helmstetter and Landeira-Fernandez, 1990. Morgan and Carrive, 2001; Walker and Carrive, 2003), arsebobs hipoTeza, rom dor-is aqtivoba kavSirSia aRmadgenel rekuperatiul qcevasTan. is, rom rekuperatiuli qceva xorcieldeba ventrolateraluri par_iT dasturdeba Semdegi cdebiT. Zlieri sisxldenis dros ventrolateraluri par-is neironebi avlenen gaZlierebul aqtivobas (Vagg et al., 2008) da ventrolateraluri par-is inaqtivacia (Cavun and Millington, 2001; Dean 2004), an masSi dor-is antagonistis naltrindolis mikroineqcia (Cavun et al., 2001) blokavs Zlieri sisxldeniT gamowveul hipotenzias. rogorc Cans, δ-

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opioiduri receptorebi monawileoben morfinul tolerantobaSi (Abdelhamid et al., 1991; Abul-Husn et al., 2007; Gomes et al., 2004), stresis dros ganviTarebul qcevaSi, magram ar monawileoben anti-nocicefciaSi (Morgan 2009), radgan deltorfinis mikroineqcia par-Si, morfin tolerantul virTagvebSi, ar iwvevs analgezias imisda miuxedavad Tu ra gziT aris gamowveuli tolerantoba, morfinis ganmeorebiTi SeyvaniT Tu qronikuli miRebiT (kanqveS Canergili kafsulebiT). amigdala da nakeris didi birTvi

ukanaskneli monacemebiT tkivilisa da endogenuri antinocicepciis sistemaSi CarTulia nuSisebri sxeuli anu amigdala. zurgis tvinis dorsalur rqebis Sreebidan nocicepturi informacia supraspinaluri struqturebis mimarTulebiT ramdenime gziT vrceldeba. erT-erTi gza aris spino-parabraqio-amigdaloiduri gza (Cauriau and Bernand, 2002), sadac nocicepturi signalebi parabraqialur birTvebSi sinapsuri gadarTvis Semdeg amigdalas centralur birTvSi, gansakuTrebiT latero-kafsularul nawilSi proecirdeba. am ukanasknelSi mravalricxovani nocicepturi neironebis arsebobis gamo, amigdalas centralur birTvs ”nociceptur amigdalas uwodeben” (Bernard et al., 1992).

amigdala farTo aferentacias Rebulobs hipokampidan da axali qerqidan da Tavis mxriv vrcel Sesavals agzavnis par-Si. is mWidrod aris dakavSirebuli rogorc funqciebiT, ise anatomiurad limburi sistemis sxva struqturebTan da iTvleba, rom mTavar rols asrulebs sensorul stimulaciebze emociuri pasuxebis, maT Soris tkivilTan dakavSirebuli SiSis formirebaSi (Davis and Whalen 2001; LeDoux, 2000; Zald, 2003). amigdala agreTve asocirdeba sinafsur plastiurobasTan, rac safuZvlad unda edos e.w. nociceptur mexsierebas adamianebsa da cxovelebSi (Maren, 2005; Phelps and LeDoux, 2005). mtkivneuli informaciis regulaciaSi amigdalas rolis kvleva intensiurad XX saukunis 80-iani wlebidan daiwyo, mas Semdeg, rac aRmoCenili iqna nocicepturi informaciis gamtari aferentuli gzebi amigdalasken (Ma and Peschanski, 1988; Bernard and Besson, 1990; Newman et al., 1996; Jasmin et al., 1997). amigdalas neironuli aqtivobis Seswavlam adamianebSi aCvena misi neironebis gaaqtiveba mtkivneuli stimulaciis sapasuxod (Zubieta et al., 2001). arsebobs garkveuli monacemebi, romelTa mixedviT amigdala warmoadgens morfinuli analgeziis mediators, radgan am struqturaSi morfinis mikroineqciis Semdeg antinocicepturi efeqti miiReba sxvadasxva saxis tkivilis testSi (Rodgers, 1978). morfinis sistemuri Seyvana Trgunavs amigdalas centraluri birTvis aqtiurobas mtkivneuli gaRizianebis sapasuxod (McGaraughty and Heinricher, 2002, Huang et al., 1993)

naCvenebia, rom virTagvebSi amigdalas medialur da centralur birTvebSi lidokainis mikroineqciis dros par-is eleqtruli stimulacia ar cvlis kudis awevis refleqsis farul periods, rac miuTiTebs, rom par-i unda warmoadgendes sareleo sadgurs amigdalas medialuri da centraluri birTvebisTvis maTi efeqtis gamosawvevad. amigdalas centraluri birTvidan gamowveuli analgeziuri efeqti realizdeba par-is µopioiduri, nakeris

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didi birTvis serotoninerguli, da lurji laqis β-adrenerguli gzebis gaaqtivebiT (Oliveira and Prado, 2001).

virTagvebSi amigdalas bazolateralur birTvSi μ-opioiduri receptorebis agonistis mikroineqcia iwvevs antinocicefcias, magram par-is ventralur ubanSi μ-opioiduri receptorebis da neirotenzinis antagonistis mikroineqcia, blokavs am analgezias. Ees faqti miuTiTebs, rom amigdalas stimulacia iwvevs antinociceptur efeqts, romelic gamowveulia par-is ventralur ubanSi opioidebisa da neirotenzinis gamoTavisuflebiT (Tershner and Helmstetter, 2000). amigdalas centraluri birTvi nociceptur aferentebs Rebulobs spino-amigdaluri gzebiT (Bernard and Besson, 1990; Jasmin et al., 1997; Ma and Peschanski, 1988; Newman et al., 1996), romlebic warmoadgens spinoTalamuri gzis kolateralebs (Burstein and Potrebic, 1993). Aaseve, aqve bolovdeba kolateralebi spino-retikulo-Talamuri da spino-ponto-Talamuri traqtidan, medialuri da intralaminaluri birTvebis Sesavlis gziT (Krout and Loewy, 2000; Petrovicky, 1990). gamoyofilia spino-trigemino-ponto amigdalas gza, romelic SesaZloa CarTulia tkivilis motivaciur-emociuri donis gansazRvraSi. savaraudod, am gzebis erT-erTi funqcias warmoadgens amigdalas centraluri birTvis antinocicepturi gzebis gaaqtiveba par-is doneze ((Bernard and Besson, 1990; Mayer, 1979; Basbaum and Fields, 1984).

bolo wlebis kvlevebiT nanaxia, rom amigdalas centraluri birTvi CarTulia rogorc mwvave, ise qronikuli tkivilis modulaciaSi, magram am procesebSi monawileobas iRebs sxvadasxva meqanizmebiT (Neugebauer, 2007). endogenur analgeziis mniSvnelovani rgolia nakeris didi birTvi, romelic anatomiurad rvm-s ekuTvnis da cnobilia, rogorc serotoninerguli analgeziuri sistemis nawili (Raja, 1995) es sistema dakavSirebulia mtkivneuli informaciis modulaciasTan, rogorc qerqqveSa, ise qerqul doneze. tkivilis SekavebaSi serotoninis roli kargad xsnis antidepresantebis efeqts, romlebic blokaven kateqolaminebis da serotoninis ukumitacebas (Porreca et al. 2002, Sari 2003). serotonin-receptorebis gaaqtiveba iwvevs kaliumis arxebis gaxsnas da kalciumis ionebis gamoTavisuflebis Sekavebas ujreTgareTa depoSi, rac Tavis mxriv akavebs

tkivils (Faber and Sah, 2003). Uukanaskneli monacemebiT nakeris did birTvSi nanaxia opioiduri receptorebi, e.i. igi CarTulia tkivilis endogenur

opioidergul regulaciaSi. nakeris didi birTvis gaRizianebiT aRiZvreba gautkivarebis efeqti.

analogiur efeqts iwvevs morfinis mikroineqciac (Morgan and Whitney, 2000; Morgan et al., 1998). nakeris didi birTvis neironebi pirdapir kavSirebs iReben par-dan. am birTvidan gamomavali daRmavali boWkoebi gaivlian dorsolateralur gzas da proecirdebian zurgis tvinis ukana rqebze (Gebhart 2004; Porreca et. al. 2002). cnobilia, rom mTavari neiroqimiuri meqanizmi, romliTac xorcieldeba nakeris didi birTvis analgeziuri efeqti, aris opioiduri da serotoninerguli. Nnakeris didi birTvis opioiduri sistema moqmedebs meTionin-enkefalinebiT, leicin-enkefalinebiT, beta-endorfinebiT da maTi antagonistia naloqsoni.

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nakeris didi birTvi mniSvnelovani rgolia tkivilis daRmaval regulaciaSi da CarTulia opioidur analgeziaSi (Fields, 2004). eleqtro-fiziologiuri maxasiaTeblebiTEda opioiduri pasuxebiT, nakeris did birTvSi gamoyofen neironebis or ZiriTad tips: pirveladi ujredebi, romlebsac ar gaaCniaT μ-receptorebi da meoradi ujredebi, romlebic Seicaven μ-receptorebs (Pan et al., 1990). nanaxia, rom opioidebi akaveben gaem-is sinafsur gadacemas pirvelad ujredebze da analgezias iwveven maTi ganSekavebiT an aqtivaciiT. Ees ujredebi daRmaval proeqciebs agzavnian zurgis tvinis ukana rqaSi da akaveben tkivilis transmisias zurgis tvinis doneze (Pan et al., 1990; ) . nakeris didi birTvis meoradi neironebi, romlebic Seicaven μ-receptorebs, aadvileben tkivilis transmisias zurgis tvinis doneze pirdapiri daRmavali proeqciebis gziT da opioidebi analgezias iwveven maTi SekavebiT (Fields. 2004; Pan et al. 2000; Porreca et al. 2002).

Amrigad rogorc vxedavT, opioidebiT gamowveul analgeziaSi CarTulia orive tipis ujredebi, opioidebi iwveven tkivilis Semakavebeli, pirveladi ujredebis ganSekavebas an aqtivacias da tkivilis gamaadvilebeli, meoradi ujredebis Sekavebas. Mmravali monacemebiT nanaxia, rom μ-receptorebis Semcveli meoradi ujredebi gaaqtivebulia mravali saxis qronikuli tkivilis dros, magram ra gzebiT xdeba am neironebiT tkivilis gaadvileba ucnobia (Porreca et al. 2002; McNally. 1999; Gebhart, 2004).

amas garda, cnobilia glutamaterguli receptorebis roli morfinuli tolerantobis ganviTarebasa da SenarCunebaSi. Mmorfin- tolerantul virTagvebis tvinis sxvadasxva ubnebis anaTlebze nanaxia, rom maTSi gazrdilia glutamatis sinafsuri gadacema (Vekovischeva et al., 2001; Trujillo and Akil, 1991; Mao et al.. 1995; Inoue et al.. 2003). am procesSi mniSvnelovan rols asrulebs agreTve camf-i (cikluri adenilat mono fosfati) da proteinkinaza-A. Mmorfin tolerantul virTagvebis nakeris didi birTvis anaTlebSiLEagreTve nanaxia glutamaterguli postsinapsuri potencialebis cvlilebebi (Bie and Pan, 2005). amasTan, glutamaturi sinafsuri gadacema gazrdilia mxolod μ-receptorebis Semcvel meorad ujredebze da es xdeba camf/proteinkinaza-AA da camf/proteinkinaza-C sistemebis gaaqtivebis gziT. amis msagvsad, camf-is analogebis aplikacia zrdis glutamatis sinafsur transmisias da agreTve, proteinkinaza-A da proteinkinaza-C agonistebis pirdapiri aplikaciac iwvevs igive afeqts (Bie and Pan, 2005, Vekovischeva et al., 2001; Inoue et al., 2003). ara-opioiduri analgetikebiT gamowveuli tolerantoba rogorc zemoT avRniSneT, opioidebis analgeziuri efeqti umTavresad gamowveulia par-Si maTi moqmedebiT (Fields et al., 2006, Ren, Dubner, 2009) da tolerantobis ganviTarebaSic ZiriTad rols es struqtura asrulebs (Lane, 2005; Heinricher, Ingram, 2009; Keay, Bundler, 2009).

uaRresad sainteresoa opioiduri da ara-opioiduri, arasteroiduli anTebis sawinaaRmdego wamlebis (asasw) urTierTqmedebis sakiTxi. asasw-ebs ganekuTvnebian ciklooqsigenazebis inhibitorebi. isini ciklooqsigenazebis inhibirebiT akaveben prostaglandinebis sinTezs, romlebic Tavis mxriv iwveven sensitizacias da nocicepturi impulsaciis gaZlierebas cnobilia, rom asasw-ebis, rogoricaa metamizoli da lizin-acetilsalicilati,

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mikroineqciebi par-Si iwvevs analgezias, xolo maTi ganmeorebiT Seyvana aSkarad gamoxatul tolerantobas (Pernia-Andrade et al., 2004; Tortorici et al., 2004; 2009; Tortorici, Vanegas, 2000; Vanegas, Tortorici, 2002). es antinocicefcia nawilobriv mainc realizdeba endogenuri opioiduri peptidebiT, radgan asasw-is par-sa da rvm-Si mikroineqciebiT gamowveuli analgezia sustdeba opioiduri antago-nistebiT (Tortorici, Vanegas, 2000; Tortorici et al., 2009 ). asasw-bis ganmeorebiTi mikroineqcia par-Si tolerantobasTan erTad iwvevs krostolerantobas morfinis mimarT da wamlis moxsnis sindroms (Tortorici, Vanegas2000; Pernia-Andrade et al., 2004; Tortorici et al., 2004; Vanegas, Tortorici, 2007). par-Si morfinis mikroineqcia zurgis tvinis doneze nocicefcias akavebs rvm-is im neironebis gavliT, romlebic pirdapir proeqciebs iZlevian zurgis tvinis ukana rqebze (Vanegas et al., 1984; Fields et al, 1995) on- neironebis SekavebiT da off-neironebis gaaqtivebiT (Fields 2004). morfin tolerantul virTagvebSi ki morfinis damatebiTi Seyvana veRar axdens on-neironebi Sekavebas da off-neironebis gaaqtivebas. amave meqanizmiT unda xorcieldebodes asasw-ebis antinocicepturi efeqtic (Tortorici et al. 2009).

metad mniSvnelovani iyo imis dadgena, monawileoben Tu ara µ-opioiduri receptorebi asasw-ebiT gamowveul analgeziaSi, da mravali cdebiT dadasturda, rom µ-opioiduri antagonistebi blokaven asasw-ebiT gamowveul analgezias (Tortorici, Vanegas, 2000; Tortorici et al., 2009; Avecado et al., 2002). rogorc morfinuli tolerantobis dros (Tortorici et al 2001), metamizol- tolerantul virTagvebSi on- da off-neironebi kargaven Cveuli maneriT moqmedebis unars, rac eleqtrofiziologiuri cdebiT iqna dadasturebuli (Tortorici et al., 2009). Tu rogor urTierTqmedeben asasw-ebi endogenur opioidebTan ucnobia, magram ueWvelia, rom gaem-erguli sinafsebi aris erT erTi SesaZlo adgili, sadac unda xdebodes maTi urTierTkavSiri. gamoTqmulia mosazreba, rom opioidebi par-Si unda iwvevdnen gaem-erguli neironebis Sekavebas da Sedegad maTi samizne ujredebis ganSekavebas. savaraudod, par-is es daRmavali Semakavebeli neironebi unda iwvevdnen antinocicepcias. (Moreu, Fields, 1986). µ-receptorebis gaaqtivebis Sedegad gaem-is sinTezis Semcireba iwvevs am ujredebSi araqidonis mJavis ujredSida koncentraciis gazrdas, romelic Semdeg gamoiyeneba sxvadasxva bioqimiur gardaqmnebSi. erT-erTi aseTi gardaqmnis Semdeg is formirdeba hepoqsilinad, romelic zrdis kaliumis arxebis ganvladobas, rasac Tan mohyveba presinafsuri gaem-erguli terminalebis hiperpolarizacia da gaem-is gamonTavisuflebis Semcireba (Vaughan et al., 1997; Vaughan 1998). par-is gamosavlis neironebis gaaqtiveba zrdis antinicicefcias, anu par – rvm – zurgis tvinis sistemiT nocicepcia modulirdeba sxvadasxva neironuli urTierTkavSirebiT (Wessendorf et al., 2006; Morgan et al., 2008; Tortorici et al., 2009)

meore molekuluri gza aris ciklooqsigenazebis moqmedeba, romlebic axdenen araqidonis mJavis prostaglandinebad gardaqmnis katalizebas. asasw-ebi blokaven ciklooqsigenazebs, riTac meti araqidonis mJava gamonTavisufldeba hepoqsilinis sinTezisTvis, rac agreTve iwvevs gaem-is gamonTavisuflebis Semcirebas (Vaughan et al., 1997; Vaughan, 1998). savaraudod par-Si asasw-ebi zustad am gziT unda moqmedebdnen da iwvevdnen antinocicefcias. magram am meqanizmisTvisac, rogorc Cans, aucilebelia opioiduri receptorebis moqmedeba imitom, rom rogorc CTOP (opioiduri

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blokatori) (Tortorici et al., 2009), ise naloqsoni (Tortorici et al., 1996; Pernia-Andrade et al., 2004) blokaven mikroineqcirebuli metamizolis moqmedebas par-Si.

jer-jerobiT ar moipoveba zusti monacemebi Tu ra gziT (uSualod Tu raime sxva gziT) axdenen metamizoli da lizin-acetilsalicilati µ-receptorebis eqspresiasA(Vanegas, Schaible 2001; Brunton et al., 2006), erT-erTi versiiT, metamizoliT gamowveuli gaem-is Semcireba ganpirobebuli unda iyos endokanabinoidebiT. endokanabinoidebi axdenen ciklooqsigenazebis blokirebas (Bisogno et al., 2005; Fowler, 2005). egzogenuri kanabinoiduri agonistebi amcireben gaem-ergul da glutamatergul sinapsur transmisias par-Si presinaptikuri transmiterebis gamonTavisuflebis SekavebiT (Vaughan et al., 2000), kanabinoid-1 agonistis AM-251 da metamizolis erToblivi mikroineqciiT par-Si qreba antonocicepturi efeqti (Vazques-Rodriguez et al., 2008). amdenad, endokanabinoidebi mniSvnelovan rols unda asrulebdnen par-Si mikroineqcirebuli araopioiodebiT gamowveul tolerantobaSi. araopioiduri da opioiduri analgetikebi SesaZloa erTnairi meqanizmebiT moqmedeben par-Si da rvm-is on- da off-neironebi monawileoben araopioidur antinocicefiisa da tolerantobis ganviTarebaSi (Tortorici et al., 2009).

nakeris didi birTvi anatomiurad mogrZo tvinis rostralur ventromedialur ubans ekuTvnis. cnobilia, rom rostraluri ventromedialuri medulas mosazRvre ubnebSi arasteroiduli anTebis sawinaaRmdego wamlebis erT-erTi warmomadgenelis, metamizolis mikroineqcia egzogenuri opiatebisa da endogenuri opioidebisa msgavsad, iwveven antinocicepcias centralur ruxi nivTierebas, nakeris did birTvsa da zurgis tvins Soris arsebul opoidergul wreebis gaaqtivebis gziT (Jones, 1996). eqsperimentebiT naCvenebia, rom morfinis mikroineqcia nakeris did birTvSi iwvevs nocicepturi refleqsis da mtkivneul stimulze moreagire spinaluri neironebis pasuxebis Sekavebas (Filds, Basbaum, 1999; Jones, 1996; Tortorici, Vanegas, 1994, 1995; Vanegas et al., 1997). garda amisa, rogorc morfinuli analgeziis SemTxvevaSi, amgvari mikroineqciebi aaqtivebs rostraluri ventromedialuri medulas e.w. off-neironebs, romlebic proeqciebs iZleva zurgis tvinis ukana rqaSi Dda axdens nocicepturi gadacemis Sekavebas mocemul doneze. amave dros axdens rostraluri ventromedialuri medulas e.w. on-neironebis Sekavebas, romlebic aseve proecirdeba zurgis tvinis ukana rqaSi, magram aadvilebs nociceptur transmisias (Filds, Basbaum, 1999; Tortorici, Vanegas, 1994, 1995).

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Tavi 2. kvlevis meTodika cxovelebi. eqsperimentebi Catarda TeTr virTagvebze, woniT 200-250 g. maTi gamoyvana xdeba fiziologiis institutis vivariumSi. cdebis msvlelobisas daculi iqna is moTxovnebi, romlebsac ayenebs tkivilis Semswavleli saerTaSoriso asociacia tkivilis eqsperimentuli Seswavlisas araanesTezirebul cxovelebSi (Zimmermann, 1983). Cveni, rogorc tkivilis Semswavleli laboratoriis eqsperimentuli kvlevis protokoli damtkicebulia iv. beritaSvilis sax. fiziologiis institutis bioeTikuri komisiis mier. intraperitoniuli ineqciebi. eqsperimentamde 3 dRis ganmavlobaSi xdeboda cxovelebis Segueba saeqsperimento garemosTan, cxoveli DdReSi erTxel 15 wuTis manZilze Tavsdeboda restreinerSi. Eeqsperimentebis seria keTdeboda xuTi uwyveti dRis ganmavlobaSi (orSabaTi-paraskevi). Aasasw-ebis intraperitoniuli ineqciidan 20 wuTis Semdeg, cxoveli Tavsdeboda restreinerSi da virTagvis kudis proqsimaluri 1/4 nawili Riziandeboda fokusirebuli sxiviT da izomeboda Tail- flick refleqsis latenturi periodi (33 Tail-flick Analgesia Meter, IITC Inc. Life Science, Woodland Hills, CA, USA) sakontrolo jgufis virTagvebs ukeTdebodaT fiziologiuri xsnaris ineqcia. Eeqsperimentis bolo dRes asasw-is ineqciidan 40 wuTis Semdeg intraperitoniulad Segvyavda morfini da Semdeg naloqsoni. wamlebi da maTi dozebi: analgini- 250mg/kg (metamizol sodium, “Sanitas”, Ltd, Lithuania) ketoralaki- 12 mg/kg (ketorolac tromethamine, 90µg/3µl, “Zee Drugs”, India) qsefokami - 1,2mg/kg lornoxicam, 12 µg/1µl, “Nycomed”, GmbH, Austria morfini - 5mg/kg (Laboratoires Stella, France) naloqsoni - 1mg/kg. (Sigma Chemical Co., Usa) fiziologiuri- 0.3 ml. (“GalichPharm” Ltd. Ukraine) anesTezia da procedura. natriumis TiopentaliT anesTeziis pirobebSi (55 mg/kg, i.p.) 25 zomis (kalibris) 12 mm sigrZis uJangavi foladis gareTa kanula (Small Parts, Inc., USA) inergeboda virTagvis Tavis tvinSi stereotaqsuli atlasis mixedviT (Paxinos & Watson, 1997), kanulis Canergvis siRrme ganisazRvreboda sakvlevi struqturidan 2 mm-is zemoT. Tavis qalaze misi damagreba warmoebda kbilis cementiT. gareTa, warmarTveli kanula daxSuli iyo uJangavi foladis mavTuliT. amis Semdgom 3 dRis ganmavlobaSi daaxloebiT 30 wuTis manZilze vaxdendiT cxovelebis saeqsperimento manipulaciebTan SeCvevas (xelSi viyvandiT, foladis mavTulis nacvlad xdeboda saineqcio kanulis Seyvana wamlisgareSe, restreinerSi Casma) artefaqtebis Tavidan asacileblad.

operaciidan sami dRis Semdeg gareTa kanulaSi vaxdendiT 29 kalibris, 14 mm sigrZis mikrosaineqcio kanulis Seyvanas, romelic dakavSirebuli iyo 1-μLLmoculobis hamiltonis SpricTan. TiToeuli Cveni Sesaswavli medikamentis (ketorolaki, qsefokami, diklofenaki da metamizoli) da fiziologiuri xsnaris Seyvana xdeboda mikrosaineqcio kanulis saSualebiT. mikroineqciidan 20 wuTis gasvlis Semdeg, e.i. daaxloebiT 10 wuTiT adre,

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vidre Cveulebriv wamlis moqmedebis efeqti miiRweva, virTagvis kudis proqsimaluri nawili¼Riziandeboda sinaTlis fokusirebuli sxiviT da izomeboda sapasuxod warmoqmnili kudis moqnevis dacviTi refleqsis (Tail-flick reflex) faruli (latenturi) periodi (33 Tail-flick Analgesia Meter, IITC Inc. Life Science, Woodland Hills, CA, USA). igive procedurebi iyo gaTvaliswinebuli aRniSnuli arasteroiduli anTebis sawinaaRmdego wamlebisa (asasw) da imave moculobis fiziologiuri xsnaris ganmeorebiTi mikroineqciebisas Tanmimdevrulad xuTi dRis ganmavlobaSi (orSabaTi-paraskevi) da agreTve morfinisa da naloqsonis erTjeradi mikroineqciebisas. morfinisa da naloqsonis Tanamimdevruli mikroineqciebi xdeboda bolo, mexuTe eqsperimentul dRes (paraskevi), Sesabamisad asasw-ebis mikroineqciebis sesiebis dasrulebidan 20-30 wuTis Semdeg.

eqsperimentebSi gamoyenebulia agreTveE hot plate testiT (39 HP, LLTC, Life science,Inc., USA) faruli periodis gansazRvra, TaTis aweva cxeli (52C0)

zedapiridan. wamlebi da maTi dozebi:

analgini- 150 µg/1µl ketoralaki- 90µg/1µl qsefokami - 12 µg/1µl, morfini - 3 µg/1µl fiziologiuri- 1µl voltareni - 75 µg/1µl klodifeni - 75 µg/1µl

histologiuri kontroli. yoveli eqsperimentis bolos mikroineqciis ubnis kontrolisTvis Segvyavda saRebavi (0,5 μLL, Pontamine Sky Blue-s najeri xsnari) da vaxdendiT virTagvebis eftanazias inhalaciiT (naxSirbadis dioqsidi). amoRebuli tvinis 10% formalinis xsnarSi moTavsebis Semdeg, mikroineqciis ubnis dasadgenad mikrotomis meSveobiT vWridiT tvinis anaTlebs. amis Semdeg stereotaqsuli atlasis (Paxinos & Watson, 1997) meSveobiT vadgendiTT Canergili kanulebis koordinatebs.¼ statistikuri analizi. kudis moqnevis da TaTis mocilebis faruli periodi ganisazRvreboda rogorc saSualo±± saSualo standartuli gadaxra. kolmogorov-smirnovis tests viyenebdiT normaluri da Tanabari ganawilebis dasadgenad. kruskal-valisis variaciuli analizi, Semdgom Tukey-Kramer da Dannet testiT gamoiyeneboda sakontrolo da testuri monacemebis Sesadareblad. statistikur sarwmunoobad miiCneoda, rodesac PP<0.05. aRniSnuli gamoTvlebi warmoebda kompiuteruli programis saSualebiT – Prism 4.03 (GraphPad Software, Inc, San Diego, CA, USA).

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Tavi 3. Sedegebi da maTi ganxilva 3.1. asasw ganmeorebiTi sistemuri (intraperitoniuli) ineqciebis gavlenis Seswavla nocicepciasa da tolerantobis ganviTarebaze Kkacobrioba saukuneebis manZilze iyenebda tirifis qerqs (willow bark), rogorc tkivilis Semamsubuqebel saSualebas. me-19 saukuneSi SeZles misi eqstraqtidan aqtiuri ingredientis salicilis mJavis gamoyofa. Semdeg scades gaeumjobesebinaT misi Tvisebebi da sinTezuri gziT miiRes acetilsalicilis mJava-aspirini, romelic gaxda ara-opioiduri analgetikebisa da NasaswD-is prototipi. am wamlis gaumjobesebis cdebma (rom hqonodaT naklebi gverdiTi efeqtebi, xangrZlivi moqmedebis unari, swrafi moqmedeba.) migviyvana mravali sxva ara-opioiduri, asasw-is aRmoCenamde, romlebic ase farTod gamoiyeneba dRes msoflioSi. Aam preparatebs aqvT sami ZiriTadiEefeqti _ analgeziuri, antipiretuli da antianTebiTi. Aantipiretuli moqmedebis centraluri meqanizmi cnobilia. HhipoTalamusSi xdeba prostoglandinebis sinTezis inhibicia. cnobilia agreTve analgeziuri moqmedebis meqanizmi periferiaze, isini blokaven ciklooqsigenazebis aqtivobas, riTac xdeba araqidonis mJavis pristoglandinebad gardaqmnis inhibireba, pristoglandiniP_2 ki uSualod aaqtivebs Tavisufal nervul daboloebebs. maTi anTebis sawinaaRmdego efeqti ganpirobebulia araqidonis mJavis prostaciklinebad gardaqmnis inhibirebiT, prostaciklenebi iwveven qsovilis SeSupebas. xolo araopioiduri asasw moqmedebis centraluri meqanizmebi naklebad aris cnobili. araopioiduri wamlebis analgeziuri efeqti nawilobriv gamowveulia centraluri nervuli sistemis struqturebze maTi zemoqmedebiT. cnobilia rom, arasteroiduli anTebis sawinaaRmdego wamlebis zurgis tvinze pirdapiri aplikacia axdens zurgis tvinis nocicepturi neironebis Sekavebas da amcirebs nociceptur pasuxebs, rogorc fxizel cxovelebSi ise simsivniT daavadebul pacientebSi (Venagas and Schaible 2001). mravalma gamokvlevam daadastura, rom FfarTod gavrcelebuli analgetikebi, metamizoli da lizin-acetilsalicilati antinocicepcias iwveven imave neironuli struqturebis gaaqtivebiT, romlebic opioidur analgeziaSi arian CarTulni – periaquedaqtis ruxi nivTiereba (par) da mogrZo tvinis rostro-ventraluri midamo (rvm) da misi axlomdebare ubnebi ( Carlsson at. al. 1986). anTebis sawinaaRmdego, ara-steroiduli wamlebi (asasw) erTis mxriv pirdapir moqmedeben zurgis tvinis nociceptur neironebze da axdenen maT Sekavebas, meores mxriv maTi mikroineqcia par-Si da mogrZo tvinis rostro-ventralur ubanSi, kerZod solisebri birTvis msxvilujredovan nawilSi da mis axlomdebare ubnebSi aaqtivebs tkivilis kontrolis daRmaval gzebs da xdeba zurgis tvinis nocicepturi neironebis Sekaveba. (Carlsson at. al. 1986; Vanegas, Tortorici, 2002), xolo am wamlebis moqmedebis blokireba SeiZleba morfinis antagonisti-naloqsoniT (Vanegas, Tortorici, 2002; Tortorici Vanegas, 2000).

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metamizolis da lizin-acetilsalicilatis ganmeorebiTi Seyvana iwvevs analgeziis progresul daqveiTebas, anu tolerantobis ganviTarebas da kros-tolerantobas morfinis mimarT (Tortorici Vanegas 2000) Ees faqtebi iZleva saSualebas vivaraudoT, rom ara-opioiduri analgetikebi moqmedeben endogenuri opioidur sistemis gaaqtivebiT (Tortorici at.al 2004). naCvenebia, rom metamizolis da lasas sistemuri da intraperitoniuli ineqcia iwvevs TF refleqsis da HP pasuxebis inhibirebas virTagvebSi. es efeqti naloqson-damokidebulia. metamizolis da lasas ganmeorebiTi Seyvana iwvevs tolerantobis ganviTarebas am wamlebis mimarT da krostolerantobas intraperitonialurad Seyvanili morfinis mimarT. metamizol da lasa_ tolerantuli virTagvebi naloqsonis ineqciis Semdeg avlenen withdrawal-is niSnebs (Pernia-Andrade at.al. 2004). am monacemebis miuxedavad ar aris dadgenili ramdenad SeiZleba ganzogaddes es faqtebi sxva asasw mimarT. kvlevisas gamoviyeneT farTod gavrcelebuli analgetikebi analgini, ketorolaki da qsefokami. Cveni mizani iyo klinikasTan miaxloebuli midgomiT, pacientebisTvis gankuTvnili dRiuri dozidan gamomdinare (wonaze gaangariSebiT) – analginis, ketorolakis da qsefokamis sistemuri (intraperitoniuli) SeyvaniT gamowveuli antinocicepciisa da maTi ganmeorebiTi Seyvanisas tolerantobis da morfinis mimarT ganviTarebuli kros-tolerantobis dadgena virTagvebSi. samive es preparati aris ara-opioiduri, magram sxvadasxva jgufis warmomadgenelia; metamizoli aris pirazolinis derivati, ketorolaki indolebis, xolo qsefokami oqsikamebis jgufs ganekuTvneba. gamoyenebulia analginis, ketoralakis da qsefokamis saineqcio formebi Semdegi sakiTxebis gasarkvevad: a) maTi ganmeorebiTi sistemuri ineqciebi iwveven TuUara tolerantobas da krostolerantobas morfinis mimarT; b) naloqsondamokidebulia Tu ara araopioiduri analgetikebiT gamowveuli analgezia. miRebulma Sedegebma aCvena, rom analginis, ketorolakis da qsefokamis sistemuri ineqcia iwvevs antinocicefcias, rac gamoixateba tail flick refleqsis latenturi periodis gazrdiT sakontrolo jgufTan SedarebiT eqsperimentis pirvel dRes (p<0.001) yoveli wamlisTvis (sur 2, 3, 4). eqsperimentis yovel momdevno dReebSi aRiniSneba antinocicepciis progresuli daqveiTeba, ise rom mexuTe dRes latentur periodis maCvenebeli utoldeba sakontrolo jgufis cxovelebis latenturi periodis maCvenebls (sur. 2 3, 4) es movlena Zalian hgavs morfinis da misi msgavsi preparatebis ganmeorebiTi Seyvanisas ganviTarebul tolerantobis efeqts da amitom es movlena moixsenieba rogorc ara-opioiduri tolerantoba (analgin-tolerantuli, ketorolak-tolerantuli da qsefokam-tolerantuli, Sesabamisad). Aara-opioidur da opioidur tolerantobas Soris kavSiris dasadgenad mexuTe dRes 20 wuTis Semdeg araopioiduri wamlis ineqciidan, samive eqsperimentul da sakontrolo jgufis virTagvebSi intraperitoniulad Segvyavs morfini da mxolod sakontrolo jgufis virTagvebi pasuxoben analgeziiT (p<0.001) (sur. 2, 3, 4) xolo analgin, ketorolak da qsefokam- tolerantuli virTagvebis tail flick refleqsis latenturi periodis maCvenebeli ar icvleba anu ganviTarda kros-tolerantoba morfinis mimarT. saeqsperimento da sakontrolo jgufis cxovelebSi Seyvanilma naloqsonma 20 wuTis Semdeg morfinis ineqciidan

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sakontrolo jgufis virTagvebSi moxsna morfinis mier ganviTarebuli antinocicepcia. saeqsperimento jgufis cxovelebSi morfinis Sedegad miRebuli latenturi periodis maCvenebeli TiTqmis ar Secvlila. kvlevis meore nawilSi eqsperimentuli jgufis virTagvebi testirebuli iyvnen analgin-naloqsoni, ketorol-naloqsoni da qsefokam-naloqsonis mimarT. eqsperimenti tardeba erTi eqsperimentuli dRis ganmavlobaSi (cxovelebSi ar aris gamomuSavebuli tolerantoba). analginis, ketorolakis da qsefokamis intraperitonul ineqciidan 20 wuTis Semdeg intraperitonulad Segvyavs naloqsoni, romelic samive eqsperimentuli jgufis cxovelebSi blokavs asasw-is mier gamowveul analgezias (sur 5) cdebma, winaswar Seyvanili naloqsonis mimarT aCvena, rom naloqsonis intraperitoniuli ineqciis Semdeg Seyvanili asasw antinociceptur efeqts veRar axorcieleben (sur 6. intaqturi cxovelebis jgufi gamoicada naloqsonis mimarT, (rogorc specialuri sakontrolo) mcired gaizarda algezia, magram statistikuri dadastureba ver miviReT (sur.7) (gaizarda nocicepciis intensivoba). Cvenma eqsperimentebma aCvena, rom araopioiduri analgetikebi analgini, ketorolaki da qsefokami iwvevs antinocicepcias cxovelebSi. Ees adasturebs sxva mecnierebis monacemebs, rom sistemurad Seyvanili an par_Si mikroineqcirebuli metamizoli da lasa (Vanegas and Toirtirici 2002; Tortorici at.al. 2000; Tortorici 2004) iwvevs antinocicepcias. Zalian mniSvnelovania is faqti, rom Cveni kvlevebiT dadasturda am wamlebis ganmeorebiTi ineqciebiT gamowveuli analgeziis Semcireba, rac gvagonebs opiodebis ganmeorebiTi ineqciebiT miRebul efeqts. paradoqsulia, rom analginiT, ketorolakiT da qsefokamiT gamowveuli tolerantoba dakavSirebulia endogenur opioidur wreebTan, razec gvafiqrebinebs krostolerantobis ganviTareba morfinis mimarT da opioidebis blokatoris, naloqsonis araopioiduri wamlebis mimarT naCvenebi antagonisturi efeqti. mniSvnelovania is faqti, rom Cvens eqsperimentebSi gamoyenebuli analginis, ketorolakis da qsefokamis antinocicepturi doza klinikur praqtikaSi miRebuli, adamianebis maqsimaluri dRiuri dozis ekvivalenturia. rogorc ucxouri (Vanegas at.al 2002; Parnia-Andrade at.al. 2004), ise Cveni kvlevebiT (Tsiklauri et.al 2005) dasturdeba, rom ara-opioiduri, arasteroiduli anTebis sawinaaRmdego wamlebis farmakologiuri efeqti asocirdeba endogenur opioidur sistemasTan da sistemurad Seyvanili am wamlebis da endogenuri opioidebis interaqtivobam SeiZleba gamoiwvios arasasurveli klinikuri Sedegi. Aara-opioiduri analgetikebiT ganpirobebuli arasasurveli Sedegebi aRwerilia klinikur praqtikaSic, am analgetikebiT xangrZlivi mkurnlobisas viTardeba wamalze damokidebuleba da maTi swrafad moxsnis SemTxvevaSi viTardeba wamlis moxsnis sindromi, romlisTvisac damaxasiaTebelia mTeli rigi vegetatiuri cvlilebebi. cnobilia, diflunizalis (salicilis mJavas derivati) mier gamowveuli farmakologiuri tolerantoba virTagvebSi da ibuprofenis (farTod gavrcelebuli asasw) _adamianebSi (Walker 1995). Cveni zemoT aRwerili, da sxva mkvlevarebis Sedegebi adasturebs Cvens varauds rom, asasw Tavis moqmedebas axorcieleben endogenuri opioiduri wreebis CarTviT. sul mcire par-Si arsebuli endogenuri antinocicepturi sistemis gaaqtivebiT, ris Sedegadac CairTveba “tkivilis kontrolis

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daRmavali sistema”, kerZod, rvm da xdeba zurgis tvinis dorsaluri rqebis neironebis Sekaveba. Oopioidebsa da Nasasw-is urTierTierTmoqmedebis erT-erTi SesaZlo meqanizmi SeiZleba iyos P par-Si maTi sinergistuli moqmedebiT ciklooqsigenazebis dablokva, da amiT araqidonis mJavis moqmedeba 12 lipooqsigenazas gzebze, es zrdis kaliumis arxebis ganvladobas, rac iwvevs gaemerguli neironebis hiperpolarizacias da amitom mcirdeba gaem-is gamonTavisufleba. saboloo efeqti arisAG samizne neironebis ganSekaveba da par-Si daRmavali antinocicepturi meqanizmis CarTva. kvlevis am nawilSi Cven vaCveneT, rom farTod gavrcelebuli araopioiduri analgetikebis,A analginis, ketorolakis da qsefokamis intraperitoniuli ineqciebi adamianisTvis maqsimaluri dRiuri dozebis ekvivalenturi dozebiT iwvevs antinocicefcias fxizel virTgvebSi. am wamlebis ganmeorebiTi Seyvana iwvevs tolerantobas da kros-tolerantobas morfinis mimarT. es faqti adasturebsNtkivilis daRmavali kontrolis struqturebis wvlils asasw -is analgeziuri efeqtis ganxorcielebaSi, rac xorcieldeba endogenuri opioiderguli meqanizmebis gaaqtivebiT. am meqanizmebis ganmeorebiTi aqtivacia iwvevs tolerantobis ganviTarebas.

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3.2. ara-opioiduri tolerantoba axalgazrda da zrdasrul virTagvebSi bolodroindeli mecnieruli kvlevebiT naCvenebia, rom farTod gavrcelebuli analgetikebi, metamizoli da lizin-acetilsalicilati antinocicefcias iwveven im struqturebis neironebis gaaqtivebiT, romlebic CarTulni arian opioidur analgeziaSi par-i, nakeris didi birTvi da rvm da misi axlomdebare ubnebi (Jones, 1996; Tortorici et al., 2003). A ara-opioiduri, ara-steroiduli anTebis sawinaaRmdego wamlebis pirdapiri aplikacia zurgis tvinze iwvevs zurgis tvinis nocicepturi neironebis Sekavebas (Vanegas, Schaible, 2001), xolo zemoT naxseneb ubnebSi maTi mikroineqcia iwvevs tkivilis mamodulirebeli daRmavali gzebis aqtivacias da zurgis tvinis nocicepturi pasuxebis inhibirebas. (Vanegas, Tortorici, 2002). Ddid interess badebs is faqti, rom morfinis antagonist naloqsons SeuZlia asasw-iT gamowveuli analgeziis dablokva (Tortorici, Vanegas, 2000; Pernia-Andrade et. al. 2004). es faqti adasturebs im mosazrebas, rom ara-opioiduri analgetikebi aaqtivebs endogenur opioidur sistemas, metamizolis da lizin-acetilsalicilatis sistemuri ineqciebi iwveven tail-flick da hot –plate pasuxebis latenturi periodis mkveTr zrdas da maTi ganmeorebiTi Seyvana iwvevs tolerantobis ganviTarebas (Tortorici 2000, Tortorici et. al., 2003). GCveni mosazrebiT, tolerantobis ganviTarebis dinamika SeiZleba iyos gansxvavebuli sxvadasxva asakSi. Aaxalgazrda cxovelebSi es movlena SeiZleba viTardebodes ufro swrafad vidre zrdasrulebSi, Aamitom SeviswavleT tolerantobis efeqtis ganviTareba droSi, analginis, ketorolakis da qsefokamisTvis axalgazrda da zrdasrul virTagvebSi cdebSi gamoyenebulia 10-12 Tvis TeTri mamri virTagvebi 200-250g woniT, zrdasrulebi da 50-60g woniT 1,5-2 Tvis axalgazrda . samive gamoyenebuli preparati aris ara-opioiduri medikamenti, magram sami gansxvavebuli asasw-is jgufis warmomadgeneli. Ees preparatebi specialurad SeirCa sxvadasxva jgufidan, radgan gvindoda gvenaxa Tu ramdenad SeiZleba ganzogaddes tolerantobis efeqti sxvadasxva aropioiduri wamlebis mimarT. O P eqsperimentis pirvel dRes, analginis, ketorolakis, qsefokamis intraperitoniuli ineqciis Sedegad orive asakobriv jgufSi (axalgazrda da zrdasruli) mniSvnelovnad izrdeba latenturi periodi fiziologiuri xsnariT damuSavebuli sakontrolo jgufis virTagvebTanA SedarebiT (p<0,001) (sur 8, 9, 10 ). axalgazrda da zrdasruli sakontrolo jgufis cxovelebi avlenen msgavs latentobas. Ppirvel dRes Aantinocicefcia aris maqsimaluri Eorive asakobriv jgufSi _ analginisTvis (p<0.001) (Fsur.8), ketorolakisTvis (p<0.001) (Fsur 9) da qsefokamisTvis (p<0.001), Sesabamisad (sur 10), magram eqsperimentis meore dRes antinocicepcia raodenobrivad gansxvavebulia axalgazrda da zrdasrul virTagvebs Soris. Aaxalgazrda virTagvebSi ineqciis Semdeg tail-flick–is latentoba TiToeuli wamlisTvis aris kontrolis ekvivalenturi ukve eqsperimentis meore dRes da bolo mexuTe dRes cxovelebi avlenen mcire hiperalgezias anu latenturi periodis maCvenebeli Semcirebulia sakontrolo jgufTan SedarebiT (sur 8, 9, 10). zrdasruli virTagvebis jgufSi antinocicefcia

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mcirdeba gradualurad, tail-flick–is latentoba ar aris mniSvnelovnad gansxvavebuli sakontrolo jgufTan SedarebiT NanalginisTvis mesame, ketorolakis da qsefokamisTvis meoTxe dRes (sur 7,8,10) axalgazrda virTagvebisgan gansxvavebiT zrdasruli cxovelebi eqsperimentis bolos ar avlenen hiperalgeziis niSnebs. Eantinocicefciis Semcireba anu tolerantobis ganviTareba msgavsia tolerantobis efeqtisa, romelic viTardeba morfinis ganmeorebiTi SeyvanebiT (Tortorici et al., 2003) da amitom am efeqts vuwodebT ara-opioidur, analgin-ketorolak da qsefokam- tolerantobas Sesabamisad. Oopioiduri agonistis morfinis mimarT SesaZlo krostolerantobis dasadgenad eqsperimentis bolo mexuTe dRes asasw-is ineqciidan erTi saaTis Semdeg orive asakobrivi jgufis virTagvebSi Segvyavs morfini. mxolod fiziologiuri xsnariT damuSavebuli cxovelebi pasuxoben analgeziiT (p<0,001), analgin-, ketorolak- da qsefokam-tolerantuli virTagvebis latenturi periodis maCvenebeli morfinis ineqciis Semdeg orive asakobriv jgufSi rCeba TiTqmis ucvleli. Ees miuTiTebs orive asakobriv jgufSi ganviTarebul krostolerantobaze morfinis mimarT (8, 9, 10). µ cxovelebis ori jgufi, (axalgazrda da zrdasruli) mas Semdeg rac maT winaswar SevuyvaneT naloqsoni, analginis (sur 11 a,b), ketorolakis (sur 12 a,b) da qsefokami (sur 13 a,b) ineqciis Sedegad ar avlenen antinocicefcias, anu opioiduri antagonisti naloqsoni blokavs asasw -is analgeziur moqmedebas rogorc tail-flick, ise hot plate testebSi. K orive asakobriv jgufSi SeviswavleT, avlenen Tu ara kros-tolerantobas asasw –is mimarT morfin- tolerantuli virTagvebi. xuTi uwyveti dRis ganmavlobaSi, rogorc axalgazrda ise zrdasrul virTagvebs gamovumuSaveTA tolerantoba morfinis mimarT. unda aRiniSnos gansxvaveba morfinis ineqciis Sedegad ganviTarebul antinocicefciis xarisxSi am or asakobriv jgufs Soris. eqsperimentis pirvel da meore dRes, zrdasrul cxovelebSi analgeziis maCvenebeli ufro didia vidre axalgazrda virTagvebSi (sur 14,15,16); mag ketorolakis da qsefokamis seriebSi zrdasrul da axalgazrda virTagvebis latentur periods Soris gansxvaveba sakmaod didia (p<0,001) (sur 15,16), xolo analginis seriaSi gansxvaveba ufro mcirea (p<0,05) (sur.14) da rac yvelaze mniSvnelovania, orive asakobrivi jgufis morfin- tolerantuli virTagvebi avlenen krostolerantobas analginis, (sur14 a,b), ketorolakis (surF15 a,b), da qsefokamis (sur16Fa,b) mimarT, rogorc tail-flick, ise hot plate testebSi. A kvlevam aCvena,rom ara-opioiduri analgetikebis (analgini ketorolaki da qsefokami ) ineqciebi orive jgufis, axalgazrda da zrdasrul, cxovelebSi iwveven antinocicefcias. Ees Sedegi srul TanxvedraSia adrindel monacemebTan, rodesac xdeba metamizolis da lizin acatil-salicilatis sistemuri Seyvana Tu mikroineqcia centralur rux nivTierebaSi (Tortorici and Vanegas, 2000; Vanegas and Tortorici, 2002). Zalian mniSvnelovania Cveni kvlevebiT naCvenebi Sedegebi, rom ara-opioiduri wamlebis ganmeorebiTi Seyvana opioidebis msgavsad iwvevs antinocicefciis daqveiTebas (Tortorici et al, 2004; Pernia-Andrade et al., 2004). Aaxalgazrda da zrdasruli virTagvebis Sedareba gvaZlevs imis Tqmis saSualebas, rom axalgazrda individebi ar arian ufro metad sensitiurebi, vidre zrdasrulebi, radgan orive jgufSi viTardebaMGmsgavsi analgezia. Mmagram

35

axalgazrda individebSi tolerantoba viTardeba ufro swrafad, radgan maTi nervuli sistema jer kidev ganviTarebis fazaSia. warmodgenili monacemebi adasturebs analgini, ketorolaki da qsefokamiT gamowveul tolerantobasa da endogenur opioidur sistemas Soris kavSirs. Oopioiduri antagonisti naloqsoni blokavs asasw –is moqmedebas orive asakobriv jgufSi. Uufro metic rogorc axalgazrda ise zrdasruli morfin-tolerantiuli virTagvebi avlenen kros- tolerantobas analginis, ketorolakis da qsefokamis mimarT. Aam faqtebze dayrdnobiT Cven vvaraudobT, rom asasw –is ganmeorebiTi SeyvanebiT gamowveul tolerantobis ganviTarebaSi CarTulia endogenuri opioiduri meqanizmebi. Ees monacemebi agreTve adasturebs sxva mkvlevarebis Sedegebs,rom endogenuri opioidebi CarTulni arian morfinis da metamizolis D(dipironis) kombinaciuri SeyvaniT gamowveul analgaziis gaZlierebaSi tail -flick refleqsis modelur cdebSi, virTagvebSi (Hernandez-Delgadillo et al. 2006). eqsperimentebSi gamoyenebuli analginis ,ketorolakis da qsefokamis analgeziuri doza klinikasTan miaxloebulia, es aris adamianisTvis maqsimaluri dRiuri dozis ekvivalenturi doza da gamoangariSebulia virTgvis sxeulis wonis mixedviT (Pong et al., 1985). warmodgenili Sedegebi sxva adrindel SedegebTan erTad Zalian mniSvnelovania medicinisTvis K sistemurad Seyvanil asasw-ebsa endogenur opioidebs Soris kavSirs SeiZleba hqondes arasasurveli klinikuri Sedegebi, tolerantobis ganviTareba, withdrawal-is sindromis riskTan erTad (Tortorici et al, 2004; Pernia-Andrade et al., 2004). cnobilia, rom diflunizalis (salicilis derivati) sistemuri Seyvana virTagvebSi, xolo ibuprofenis, kargad cnobili da farTod gavrcelebuli asasw,adamianebSi iwvevs farmakodinamikur tolerantobas (Walker 1995). Cveni adrindeli (Tsiklauri and Tsagareli, 2005; Tsiklauri et al., 2005) da axali monacemebiTac naCvenebia asasw-is SesaZlo interaqtivoba endogenur opoiodebTan, magaliTad centralur rux nivTierebaSi opioiduri meqanizmebis gaaqtiveba, rac Tavis mxriv CarTavs damaval gzebs rostralur ventro-medialur medulaSi da zurgis tvinis dorsalur rqebSi.DA (Hernandez-Delgadillio and Cruz, 2006; Pernia-Andrade et al., 2004; Tortorici et al., 2003; Vanegas and Tortorici, 2002). D erT-erTi meqanizmi SeiZleba iyos asasw-ebis da opioidebis interaqtivoba, kerZod ciklooqsigenazebis blokireba ris Sedegadac gamonTavisufldeba araqidonis mJava da 12-lipooqsigenazas gzebze moqmedebis gziT zrdis kaliumis arxebis ganvladobas, Sedegad izrdeba gaemerguli neironebis hiperpolarizacia da gaem-s gamonTavisufleba da ganSekavdeba samizne neironebi periaquadaqtalSi rac iwvevs daRmavali antinicicepturi meqanizmebis gaaqtivebas. analginis ketorolakis da qsefokamis intraperitonuuli ineqcia klinikasTan miaxlovebuli dozebiT axalgazrda da zrdasrul virTagvebSi iwvevs antinocicefcias, ganmeorebiT Seyvanas mivyavarT am wamlebis mimarT tolerantobis da morfinis mimarT kros-tolerantobis ganviTarebamde. axalgazrda individebSi es movlena viTardeba ufro swrafad vidre zrdasrulebSi.

36

analgini

02468

101214161820

1 2 3 4 5dReebi

lat

entoba,wm

zrdasruli

axalgazrda

sur. 8 zrdasrul da axalgazrda virTagvebSi tail-flick-is latenturi periodis cvlileba analginis ganmeorebiTi ineqciebis pirobebSi.

37

ketorolaki

0

5

10

15

20

25

1 2 3 4 5dReebi

lat

entoba. wm

zrdasruli

axalgazrda

sur. 9 zrdasrul da axalgazrda virTagvebSi tail-flick-is latenturi periodis cvlileba ketorolakis ganmeorebiTi ineqciebis pirobebSi.

38

qsefokami

0

5

10

15

20

25

30

1 2 3 4 5dReebi

lat

entoba. w

m

zrdasruli

axalgazrda

sur. 10 zrdasrul da axalgazrda virTagvebSi tail-flick-is latenturi periodis cvlileba qsefokamis ganmeorebiTi ineqciebis pirobebSi.

39

0

2

4

6

8

lat

entoba w

m.

fiziologoiurinaloqsonianalgini

axalgazrdaA

zrdasruli

sur. 11 (A) analginis ineqciiT gamowveuli tail-flick-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi.

40

0

2

4

6

8

lat

entoba

wm.

fiziologiurinaloqsonianalgini

axalgazrda zrdasruliB

sur. 11 (B) analginis ineqciiT gamowveuli hot plate-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi.

41

0

2

4

6

8

lat

entoba

wm.

fiziologiurinaloqsoniketorolaki

Aaxalgazrda zrdasruli

sur. 12 (A) ketorolakis ineqciiT gamowveuli tail-flick-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi.

42

0

2

4

6

8

lat

antoba

wm.

fiziologiurinaloqsoniketorolaki

zrdasruliBaxalgazrda

sur. 12 (B) ketorolakis ineqciiT gamowveuli hot plate-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi

43

0

2

4

6

8

lat

entoba wm.

fiziologiurinaloqsoniqsefokami

axalgazrdazrdasruliA

sur. 13 (A) qsefokamis ineqciiT gamowveuli tail-flick-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi

44

0

2

4

6

8

lat

entoba

wm.

fiziologiuri

naloqsoni

qsefokami

axalgazrda zrdasruli

sur. 13 (B) qsefokamis ineqciiT gamowveuli hot plate-is latenturi periodis cvlileba axalgazrda da zrdasrul virTagvebSi naloqsonis winaswari Seyvanis pirobebSi.

45

morfini/analgini

0

2

4

6

8

10

fiz 1 2 3 4 5 analg

dReebi

latantoba wm.

zrdasruli

axalgazrda

A

***

sur. 14 (A) morfin-tolerantul virTagvebSi tail-flick-is latenturi periodis cvlileba analginis ineqciis Semdeg

46

morfini/analgini

0

2

4

6

8

10

12

fiz 1 2 3 4 5 analg

dReebi

latentoba wm.

zrdasruli

axalgazrda

B

** *

sur. 14 (B) morfin-tolerantul virTagvebSi hot plate-is latenturi periodis cvlileba analginis ineqciis Semdeg

47

morfini/ketorolaki

0

2

4

6

8

10

12

14

fiz 1 2 3 4 5 ketor

dReebi

latentoba wm.

zrdasruli

axalgazrda

A

**

****

sur. 15 (A) morfin-tolerantul virTagvebSi tail-flick-is latenturi periodis cvlileba ketorolakis ineqciis Semdeg.

48

morfini/ketorolaki

0

2

4

6

8

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12

fiz 1 2 3 4 5 ketor

dReebi

latentoba wm. zrdasruli

axalgazrda

B

***

**

sur. 15 (B) morfin-tolerantul virTagvebSi hot-plate-is latenturi periodis cvlileba ketorolakis ineqciis Semdeg.

49

morfini/qsefokami

0

2

4

6

8

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12

14

fiz 1 2 3 4 5 qsef

dReebi

latentoba wm. zrdasruli

axalgazrda

A

***

**

sur. 16(A) morfin-tolerantul virTagvebSi tail-flick-is latenturi periodis cvlileba qsefokamis ineqciis Semdeg

50

morfini/qsefokami

0

2

4

6

8

10

12

14

fiz 1 2 3 4 5 qsef

dReebi

latentoba wm

zrdasruli

axalgazrda

B

*****

*

sur. 16(B) morfin-tolerantul virTagvebSi hot-plete-is latenturi periodis cvlileba qsefokamis ineqciis Semdeg.

51

3. 3 amigdalas centralur birTvSi asasw-ebis ganmeorebiTi uni- da bilateraluri mikroineqciebiT

gamowveuli tolerantoba. tkivilis gancda aris uaryofiTi emocia. ukasknel wlebSi emocia ganixileba ara rogorc tkivilis paraleluri, aramed rogorc tkivilis modulaciaSi monawile procesi (Davis and Whalen 2001; LeDoux 2000; Zald 2003). tkivilis emociuri SegrZnebis modulators warmoadgens amigdala anu nuSisebri kompleqsi, igi farTo Sesavlebs Rebulobs Hhipokampidan da neokortaqsidan da Tavis mxriv warmoadgens par-is aferentebis ZiriTad wyaros (Aggleton1996), bazolateralur amigdalaSi opioidebis agonistebis mikroineqciiT gamowveuli analgezia iblokeba centralur rux nivTierebaSi lidokainiT ganpirobebuli inaqtivaciiT an opioiduri antagonistebis mikroineqciiT (Helmstetter et.al.1998; Pavlovic at.al.1996; Rivzi at al 1991). amigdalas centraluri birTvi nociceptur Sesavlebs iRebs rogorc pirdapir zurgis tvinidan, ise arapirdapir, tvinis xidis parabraqialuri birTvebis gavliT zurgis tvinis dorsaluri rqebidan (Gauriau, Bernard 2002; Gauriau, Bernard 2004). zogierTi avtori amigdalas centralur birTvs tkivilis modulatoruli wreebis integralur komponentad miiCnevs. D es birTvi mniSvnelovania nocicepturi refleqsebis morfinis sistemuri SeyvaniT gamowveul supresiaSi, (Manning and Mayer 1995). morfinis sistemuri Seyvana Trgunavs amigdalas centraluri birTvis aqtiurobas mtkivneuli gaRizianebis sapasuxod (Huang et al. 1993), adamianebSi amigdalas neironuli aqtiurobis Seswavlamac aCvena misi neironebis gaaqtiveba mtkivneuli stimulaciis sapasuxod (Zubieta et al, 2001). Aamigdalas centralur birTvSi aRmoCenilia didi raodenobiT opioiduri receptorebi da endogenuri opioidebi, dinorfini da enkefalini. Cveni kvlevis mizans warmoadgenda dagvedgina araopioiduri analgetikebis, analginis, ketorolakisa da qsefokamis, mikroineqcia amigdalas centralur birTvSi iwvevs Tu ara analgezias da ganmeorebiTi mikroineqciebisas viTardeba Tu ara tolerantoba da kros-tolerantoba morfinis mimarT anu gansazRvra imisa Tu ramdenad aris CarTuli amigdalas centraluri birTvi endogenuri opioiduri sistemiT regulirebad tkivilis daRmaval modulaciaSi. par-i da rvm warmoadgens opioiduri analgetikebis moqmedebis centralur substrats. Eendogenuri opioiduri peptidebi ganTavsebulni arian neironis somaSi an terminalur daboloebebSi am neironuli badis sxvadasxva komponentebSi. Ees wreebi asrulebs did rols opioidur analgeziasa da opioidur damokidebulebaSi (Fields at.al.2006). naCvenebia, rom ara-opioiduri analgetikebis, metamizolis da lizin- acetilsalicilatis mikroineqciebi tvinis zogierT ubanSi, gansakuTrebiT par-Si da rvm-Si, iwvevs antinicicefcias tolerantobis efeqtTan erTad. (Jones 1996 ;Pernia-andrade at. al. 2004; Tortorici at. al. 2000; Tortorici at.al 2004). Cveni wina kvlevebiTac naCvenebia analginis, ketorolakis da qsefokamis ganmeorebiTi intraperitiniuli ineqciebis Sedegad ganviTarebuli tolerantobis efeqti (Tsagareli at.al.2004; Tsiklauri at al. 2006; Tsiklauri at. al. 2006).Aam kvlevebis erTad aRebuli Sedegebi miuTiTebs, rom ara-steroiduli, anTebis sawinaaRmdego wamlebis moqmedebis

52

Sedegad tkivilis kontrolis daRmavali gzebis gaaqtiveba unda xdebodes endogenuri opioiderguli meqanizmebis CarTviT. Kkvlevis am nawilSi vecadeT gagverkvia analginis, ketorolakis da qsefokamis mikroineqciebi amigdalas centralur birTvSi iwveven Tu ara tolerantobas virTagvebSi da rogor aris is CarTuli tkivilis makontrolebel sistemaSi. Catarebulma eqsperimentebma uCvenes, rom acb-Si araopioiduri, arasteroiduli anTebis sawinaaRmdego wamlebis (asasw) mikroineqcia, unilateralurad (marcxena mxares) iwvevs mkveTrad gamoxatul antinocicefcias, rogorc tail flick, ise hot plate testSi, samive preparatisTvis sakontrolo jgufTan SedarebiT (sur. 16 a da 17a), analginisTvis (p<0.001), ketorolakisTvis (p<0.001) da qsefokamisTvis (p<0.001), magram Semdgomi oTxi dRis ganmavlobaSi aRniSnuli wamlebis ganmeorebiTi mikroineqciebisas aRiniSneba antinocicefciis gradualuri daqveiTeba ise, rom mexuTe dRes latenturi periodi utoldeba fiziologiuri xsnariT damuSavebuli cxovelebis latenturi periodis maCvenebels. es movlena msgavsia par-Si morfinis ganmeorebiTi mikroineqciebis Sedegad ganviTarebuli tolerantobis efeqtisaM(M. Morgan et,al. 2005; V.Tortorici et,al. 2003), da mas ara-opioidur tolerantoba ewodeba. Eeqsperimentis bolo mexuTe dRes sakontrolo da eqsperimentuli jgufis cxovelebi imave ubanSi mikroineqcirebulni arian morfinis hidroqloridiT da mxolod fiziologiuri xsnariT damuSavebuli virTagvebi pasuxoben antinocicefciiT (p<0.001). ara-opioidur tolerantuli cxovelebis latenturi periodis maCvenebeli morfinis mikroineqciis Semdeg ar icvleba, anu aCveneben kros-tolerantobas morfinis mimarT (sur16a da17a). A amigdalas centralur birTvSi bilateraluri mikroineqciebi agreTve zrdis analgezias, eqsperimentis pirvel dRes, analginisTvis (p<0.001), ketorolakisTvis (p<0.001) da qsefokamisTvis (p<0.001) orive testSi (sur16bªda17b). Tumca meore dRes, ganmeorebiTi mikroineqciis Semdeg, latenturi periodis maCvenebeli, iseve rogorc unilateraluri mikroineqciebisas, iwyebs Semcirebas da mexuTe dRes antinocicefciis xarisxi msgavsia sakontrolo jgufis virTagvebis latenturi periodisa. gansxvaveba unilateralur da bilateralur mikroineqciebs Soris TvalsaCinoa eqsperimentis pirvel dRes, latenturi periodi ufro didia bilateraluri mikroineqciebis dros (sur 16a da 16b; 17a da 17b). amitom SegviZlia davaskvnaT, rom roca amigdalas centraluri birTvis orive mxare (marjvena da marcxena) CarTulia erTi amocanis gadawyvetaSi, pasuxebis magnituda ufro didia, vidre maSin, roca isini moqmedeben cal-calke. asasw-is bilateraluri mikroineqciebis Semdegadac viTardeba kros-tolerantoba morfinis mimarT.(16b; 17b) Catarebulma eqsperimentebma aCvena, rom amigdalas centralur birTvSi analginis, ketorolakis da qsefokamis mikroineqciebi iwveven antinocicefcias fxizel virTagvebSi. Ees kidev erTxel adasturebs Cveni adrindeli kvlevebis monacemebs (Tsiklauri et.al. 2006) roca intraperitoniulad Segvyavs asasw da sxva avtorebis monacemebs (Pernia-andriade 2000; Tortorici 2004 ) roca centralur rux nivTirebaSi keTdeba mikroineqciebi. Zalian mniSvnelovania, rom rogorc Cveni, ise kolegebis monacemebiT naCvenebia, rom amigdalas centralur birTvSi asasw-isN ganmeorebiTi mikroineqciebi iwveven

53

analgeziis daqveiTebas, rac Zalian gvagonebs opioidebis ganmeorebiTi Seyvanebis Sedegad ganviTarebulQefeqts. Ddid gaocebas iwvevsG opioiderguli meqanizmebis CarTuloba asasw-iTNgamowveul tolerantobaSi, radgan tradiciulad iTvleba rom opioduri da ara-opioiduri wamlebis ujreduli da molekuluri aqtivoba aris gansxvavebuli. sainteresoa, opioidebis msgavsadN asasw-is SeyvanebiT gamowveuli tolerantobis efeqti, rac gamoixateba antinocicepturi efeqtis progresul daqveiTebaSi. da ufro metic , asasw-tolerantuli virTagvebi kros-tolerantulebi arian morfinis mimarT (Tsagareli et.al.2005;Tsiklauri et. al. 2006; Pernia-andriade 2000, Tortorici 2004), Cveni eqsperimentebis Sedegad amigdalas centralur birTvSi ganviTarebuli tolerantoba miuTiTebs rom es efeqti realizebuli unda iyos par-idan gamomavali tkivilis kontrolis daRmavali gzebis gaaqtivebiT, romlebis eSvebian zurgs tvinis dorsalur rqebis doneze Dda miuTiTebs, rom amigdalas centraluri birTvi CarTuli unda iyos tkivilis kontrolisa endogenuri wreebis moqmedebaSi. es Sedegebi agreTve miuTiTebs, rom par-Tan da rvm-Tan erTad amigdalas centraluri birTvi endogenuri antinocicepturi sistemis mniSvnelovani ubania. Mmisi gaaqtiveba iwvevs tkivilis kontrolis daRmavali gzebis amoqmedebas da Sedegad nocicepturi transmisiis Sekavebas. Mmeores mxriv, Cveni monacemebi sxva avtorebis monacemebTan erTad miuTiTebs asasw-isa da endogenuri opioidebis urTierTkavSirze da ara-opioiduri tolerantobis SesaZlo damokidebulebaze opioidur tolerantobasTan, razec miuTiTebs morfinis mimarT kros-tolerantoba. warmodgenilma gamokvlevebma daadastures Cveni adrindeli Sedegebi, rodesac vaxdendiT aRniSnuli ara-steroiduli anTebis sawinaaRmdego wamlebis intraperitonealur ineqcias, da agreTve sxva avtorTa monacemebi, romlebic awarmoebdnen metamizolisa da acetilsalicilis ineqcias crn-Si. ufro metic, CamoTvlili asasw-is mimarT tolerantoba icvleba kros-tolerantobiT morfinis mimarT, rasac adgili aqvs opioiduri preparatebiT moqmedebis dros. es faqtebi miuTiTeben garkveul kavSirze araopioidur da opioidur wamlebs Soris.

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3. 4. amigdalas centralur birTvSi voltarenis da klodifenis mikroineqciebiT gamowveuli tolerantobis Seswavla Hot plate testiT.

virTagvebis calke jgufi gamoicada hot-plate testiT. amigdalas centralur birTvSi unilateralurad da bilateralurad cxovelebi iyvnen mikroineqcirebulni voltareniT 75mkg/3mkl (diclofenac sodium, “Novartis Pharma” AG, Switzerland) da klodifeniT75mkg/3mkl (diclofenac sodium ” E.I.PI”Comp.Egypt) orive preparatis unilateraluri (marcxena ubani) mikroineqciebi amigdalas centralur birTvSi iwvevs antinocicefcias, rac gamoixateba hot-Plate testis latenturi periodis gazrdiT sakontrolo jgufis (fizilogiuri xsnariT damuSavebulebi) virTagvebTan SedarebiT. eqsperimentis pirvel dResHklodifenisTvis p<0.001 da voltarenisTvis p<0.05 (sur 2) (ANOVA:F(2,19)=11.95, P=0.0003) magram, ganmeorebiTi mikroineqciebis Semdeg antinocicepturi efeqti progresulad iwyebs daklebas, meoTxe dRes hot-Plate testis latenturi periodis maCvenebeli sakontrolo maCveneblis msgavsia. mexuTe dRees imave ubanSi Segvyavs morfinis hidroqloridi da mxolod sakontrolo jgufis virTagvebi pasuxoben antinocicefciiT, (sur. 18) klodifen da voltaren- tolerantuli virTagvebi aCveneben kros-tolerantobas morfinis mimarT. Bbilateraluri mikroineqciebi amigdalas centralur birTvSi agreTve zrdis latenturi periodis maCvenebels sakontrolosTan SedarebiT klodifenis da voltarenisTvis (p<0.001) (sur19) (ANOVA: F(2.19=25,P<0.0001). Eeqsperimentis meore dRes, ganmeorebiTi mikroineqciis Semdeg, hot-plate-is latentoba Semcirebulia ( ANOVA:F(2,19)=11.67, P=0.0004) klodifenisTvis (p<0.001) da voltarenisTvis (p<0.01) Sesabamisad (sur 19) meoTxe da mesuTe dRisTvisHP hot-plate latentoba msgavsia im virTagvebis latenturi periodis romlebic fiziologiuri xsnariT, bilateralurad iyvnen mikroineqcirebulni.Bbilateralur da unilateralur mikroineqciebs Soris gasxvaveba kargad Cans eqsperimentis pirvel da meore dRes. bilateraluri ineqcia iwvevs ufro Zlier efeqts unilateralurTan SedarebiT (p<0.05). (sur 18-19), rac miuTiTebs, rom roca amigdalas centraluri birTvis orive nawili (marjvena da marcxena) CarTulia endogenur analgeziur meqanizmebSi. bilateraluri mikroineqciebisas iseve viTardeba kros-tolerantoba rogorc unilateraluri Seyvanebisas. ucxoeli avtorebisa da Cvens mier miRebuli monacemebi adastureben garkveuli kavSiris arsebobaze araopiodur analgetikebis moqmedebasa da endogenur opioidur sistemas Soris. savaraudod Cvens mier gamoyenebuli araopioiduri, anTebis sawinaaRmdego wamlebi unda moqmedebdnen lokalur opioidebze, romelTa CarTviTac unda xorcieldebodes garkveulwilad maTi analgeziuri da miT umetes tolerantobis efeqtebi.

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sur. 16 a. amigdalas centralur birTvSi asasw-ebis unilateraluri mikroineqciebiT gamowveuli tail-flick refleqsis latenturi periodis cvlileba.

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sur 16 b. amigdalas centralur birTvSi asasw-ebis bilateraluri mikroineqciebiT gamowveuli tail-flick refleqsis latenturi periodis cvlileba.

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sur 17a. amigdalas centralur birTvSi asasw-ebis unilateraluri mikroineqciebiT gamowveuli hot plate refleqsis latenturi periodis cvlileba.

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sur 17b. amigdalas centralur birTvSi asasw-ebis bilateraluri mikroineqciebiT gamowveuli hot plate refleqsis latenturi periodis cvlileba.

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sur 18. amigdalas centralur birTvSi klodifenis da voltarenis unilateraluri mikroineqciebiT gamowveuli hot plate refleqsis latenturi periodis cvlileba.

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sur 19. amigdalas centralur birTvSi klodifenis da voltarenis bilateraluri mikroineqciebiT gamowveuli hot plate refleqsis latenturi periodis cvlileba.

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sur 20. A amigdalas centralur birTvSi

unilateraluri mikroineqciis ubani.

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sur. 21. asasw-ebis amigdalaSi bilateraluri mikroineqciis ubnebi. Paxinos &Watson-is atlasis mixedviT (1997). distancia bregmadan– 2.12 mm (A), -2.30 mm (B), -2.56 mm (C), da -2.80 mm (D), Sesabamisad.

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3.5 periaqueduqtis ruxi nivTierebis (par) ventro-lateralur ubanSi asasw –is ganmeorebiTi mikroineqciis Sedegebi. Sua tvinis periaqueduqtis ruxi nivTiereba, par-i, aris cns-is im wreebis nawili, romlebic axorcieleben nocicepturi transmisiis kontrols zurgis tvinis doneze rvm-is gavliT. Ppar-rvm sistema aris opioiduri analgetikebis aqtivobis da narkotikuli damokidebu;lebis ganviTarebis centraluri substrati. endogenuri opioiduri peptidebi ganTavsebulni arian neironis somaSi an terminalur daboloebebSi neironuli badis sxvadasxva komponenetebSi (Fields 2004; Henricher and Ingram, 2009; Heinricher et al. 2009; Ren and Dubner, 2009) virTagvebSi morfinis an dipironis mikroineqcia par-Si iwvevs tkivilis gamaadvilebeli “ON” ujredebis aqtivobis Sesustebas da tkivilis Semakavebeli ‘’OFF” ujredebis aqtivobis gazrdas, rasac mosdevs antinocicefcia (Fields 2004; Tortorici et al.2009). araopioiduri analgetikebi, lizin-acetilsalicilati da metamizoli, opioidebis msgavsad par-Si ganmeorebiTi Seyvanisas iwveven tolerantobas opioiderguli gzebis gaaqtivebiT (Tortorici et al.2009 Tortorici et al 2004, Tortorici and Vanegas 2000. Pernia-Andrade et al. 2004, Vanegas and Tortorici 2002). Ppar-i da misi daRmavali proeqciebi nakeris did birTvsa da rvm-Si tkivilis kontrolis daRmavali antinocicepturi sistemis ZiriTadi komponentebia ( Fields et al 2006; Henricher and Ingram 2009; Heinricher et al. 2009; Ren and Dubner 2009). Cveni adrindeli kvlevebiTac naCvenebia asasw-ebis, analginis, ketorolakis da qsefokamis ganmeorebiTi intraperitoniuli ineqciebiT gamowveuli tolerantoba da krostolerantoba morfinis mimarT (Tsagareli at al. 2005; Tsiklauri at al.. 2006; Tsiklauri at al. 2008; Tsiklauri and Tsagareli 2006; Tsiklauri at al. 2010), Aamave preparatebis mikroineqciebiT amigdalas centralur birTvSi gamowveuli tolerantoba maT mimarT da kros-tolerantoba morfinis mimarT (Tsagareli at al. 2010; Tsiklauri at al. 2008;. Tsiklauri at al. 2009). erTad aRebuli es Sedegebi miuTiTebs, rom ara-opioiduri arasteroiduli anTebis sawinaaRmdego wamlebi analgezias axorcieleben endogenuri opioiderguli meqanizmebis gaaqtivebiT (Henricher and Ingram 2009; . Hernández-Delgadillo and Cruz 2006) kvlevis am nawilSi SeviswavleT .analginis, qsefokamis, ketorolakis da klodifenis mikroineqciebiT par-Si gamowveuli tolerantoba mamr virTagvebSi. Sua tvinis periaqueduqtis ruxi nivTiereba, par-i, aris cns-is im wreebis nawili, romlebic axorcieleben nocicepturi transmisiis kontrols zurgis tvinis doneze rvm-is gavliT. Ppar-rvm sistema aris opioiduri analgetikebis aqtivobis da narkotikuli damokidebu;lebis ganviTarebis centraluri substrati. endogenuri opioiduri peptidebi ganTavsebulni arian neironis somaSi an terminalur daboloebebSi neironuli badis sxvadasxva komponenetebSi (Fields 2004; Henricher and Ingram, 2009; Heinricher et al. 2009; Ren and Dubner, 2009) virTagvebSi morfinis an dipironis mikroineqcia par-Si iwvevs tkivilis gamaadvilebeli “ON” ujredebis aqtivobis Sesustebas da tkivilis Semakavebeli ‘’OFF” ujredebis aqtivobis gazrdas, rasac mosdevs

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antinocicefcia (Fields 2004; Tortorici et al.2009). araopioiduri analgetikebi, lizin-acetilsalicilati da metamizoli, opioidebis msgavsad par-Si ganmeorebiTi Seyvanisas iwveven tolerantobas opioiderguli gzebis gaaqtivebiT (Tortorici et al.2009 Tortorici et al 2004, Tortorici and Vanegas 2000. Pernia-Andrade et al. 2004, Vanegas and Tortorici 2002). Ppar-i da misi daRmavali proeqciebi nakeris did birTvsa da rvm-Si tkivilis kontrolis daRmavali antinocicepturi sistemis ZiriTadi komponentebia ( Fields et al 2006; Henricher and Ingram 2009; Heinricher et al. 2009; Ren and Dubner 2009). Cveni adrindeli kvlevebiTac naCvenebia asasw-ebis, analginis, ketorolakis da qsefokamis ganmeorebiTi intraperitoniuli ineqciebiT gamowveuli tolerantoba da krostolerantoba morfinis mimarT (Tsagareli at al. 2005; Tsiklauri at al.. 2006; Tsiklauri at al. 2008; Tsiklauri and Tsagareli 2006; Tsiklauri at al. 2010), Aamave preparatebis mikroineqciebiT amigdalas centralur birTvSi gamowveuli tolerantoba maT mimarT da kros-tolerantoba morfinis mimarT (Tsagareli at al. 2010; Tsiklauri at al. 2008;. Tsiklauri at al. 2009). erTad aRebuli es Sedegebi miuTiTebs, rom ara-opioiduri arasteroiduli anTebis sawinaaRmdego wamlebi analgezias axorcieleben endogenuri opioiderguli meqanizmebis gaaqtivebiT (Henricher and Ingram 2009; . Hernández-Delgadillo and Cruz 2006) kvlevis am nawilSi SeviswavleT .analginis, qsefokamis, ketorolakis da klodifenis mikroineqciebiT par-Si gamowveuli tolerantoba mamr virTagvebSi.HP asasw-ebis da fiziologiuri xsnaris mikroineqcia histologiurad lokalizebuli iyo par –is ventro-lateralur nawilSi (sur. 22). asasw-ebis mikroineqciebi par –Si iwvevs antinocicefcias, rac gamoixateba tail flick da hot plate pasuxebis gazrdiT sakontrolo maCvenebelTan SedarebiT. kerZod, tail flick–is latentoba sarwmunod aris gazrdili analginisTvis, [ANOVA:F(6,33)=28.487, (P<0.0001)], pirvel da meore saeqsperimento dRes (p<0.01) (sur 23 A). hot plate-is latentoba analginisTvis agreTve sarwmunod gazrdilia [ANOVA: F(6,33)=31.377, (P<0.0001)], pirvel da meore saeqsperimento dRes (p<0.01) (sur. 23 B). danarCeni asasw-ebisTvis tail flick da hot plate gazrdilia sami dRis ganmavlobaSi (p<0,01). statistikuri monacemebi aCvenebs sarwmuno cvlilebebs, tail flick testSi latentoba klodifenisTvis [ANOVA:F(6,33)=27.446, (P<0.0001)], ketorolakisTvis [ANOVA:F(6,33)=34.198, (p<0.0001)] da qsefokamisTvis [ANOVA:F(6,33)=46.26 (P<0.0001)], Sesabamisad (sur. 23A). hot plate testSic latentoba aseve icvleba klodifenisTvis [ANOVA: F(6,33)=29.462, (P<0.0001)], ketorolakisTvis [ANOVA: F(6,33)=44.71, (P<0.0001)], da qsefokamisTvis [ANOVA:F(6,33)=60.351, (P<0.0001)], Sesabamisad (sur. 23 B). magram, am wamlebis ganmeorebiTi mikroineqciebisas antinocicepturi efeqti mcirdeba, ise rom, eqsperimentis meoTxeEdRes da gansakuTrebiT mexuTe dRes tail flick da hot plate latentoba fiziologiuri xsnariT ganmeorebiT mikroineqcirebuli virTagvebis jgufis saSualo ( me-5 dRis) maCveneblis msgavsia. es efeqti par-Si morfinis da misi msgavsi preparatebis ganmeorebiTi mikroineqcibisas ganviTarebuli tolerantobis msgavsia ( Morgan et al. 2005; Tortorici et al. 2004). eqsperimentis mexuTe dRes asasw-ebis mikroineqciidan erTi saaTis Semdeg intraperitoniulad Segvyavs naloqsoni (μ-opioiduri

65

antagonisti). tail flick da hot plate latentoba ar icvleba rogorc ara-opioid tolerantul ise sakontrolo jgufis cxovelebSi (sur .23 A,B.) Cvens mier miRebuli Sedegebi kidev erTxel miuTiTebs garkveuli kavSiris arsebobaze araopiodur analgetikebis moqmedebasa da endogenur opioidur sistemas Soris.

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sur 22 . par-Si asasw-is mikroineqciis ubnebi Paxinos &Watson-is atlasis mixedviT. distancia bregmadan -4.8 mm (A), -5.2 (B) da -5.6 (C), Sesabamisad.

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sur. 23 a. par-Si asasw-ebis ganmeorebiTi mikroineqciebisas tail- flick refleqsis faruli periodis cvlileba. testiT.

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sur. 23 b. par-Si asasw-ebis ganmeorebiTi mikroineqciebisas hot- plate refleqsis faruli periodis cvlileba. testiT

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3.6.N nakeris didi birTvis da rostro ventraluri medulas monawileoba ara-opioidur analgeziaSi. rogorc disertaciis wina nawilSi iqna aRniSnuli, nakeris didi birTvi da momijnave retikuluri formacia ekuTvnis rostralur ventro-medialur medulas. rvm ki warmoadgens cns-is im wreebis nawils, romlebic axorcieleben nocicepturi transmisiis kontrols zurgis tvinis doneze. Ppar-rvm sistema aris opioiduri analgetikebis aqtivobis da narkotikuli damokidebu;lebis centraluri substrati da endogenuri opioiduri peptidebi ganTavsebulni arian neironis somaSi an terminalur daboloebebSi am neironuli badis sxvadasxva komponenetebSi (Fields. 2004; Henricher and Ingram, 2009; Heinricher et al. 2009; Ren and Dubner, 2009; Heinricher et,al.2009;. Tortorici et,al.2004; Tsiklauri et,al.2010). par-i da misi daRmavali proeqciebi nrm-Si da rvm-Si tkivilis kontrolis daRmavali antinocicepturi sistemis ZiriTad rgols warmoadgens. (Fields et, al. 2006; Henricher and Ingram 2009: 593-626. Heinricher et, al. 2009, Ren and, Dubner 2009), dipironis mikroineqcia par-Si amcirebs tkivilis gamaadvilebeli on-ujredebis aqtivobas da zrdis tkivilis Semakavebeli off-ujredebis aqtivobas, rasac mivyavarT antinocicepciamde, (Fields et, al. 2004; Tortorici et, al. 2009) , msgavsi antinocicepturi efeqti miiReba morfinis ndb-_Si ( Jones 1996 ) da rvm_Si ( Henricher 1992) mikroineqciiT. rvm-Si ganmeorebiTi mikroineqciebisas tolerantobis ganviTareba ar SeiniSneba (Morgan 2005),Uufro metic rvm-is inaqtivacia ar Trgunavs par-Si morfinis ganmeorebiTi mikroineqciebisas tolerantobis ganviTarebas da morfinis ganmeorebiTi sistemuri Seyvanisas ar viTardeba tolerantoba Tu par-Si dablokilia opioiduri receptorebi. rogorc Cans,Ppar-i warmoadgens mTavar struqturas rogorc morfinuli ise ara-opioiduri tolerantobis ganviTarebaSi. (Tortorici et, al,2009; Tortorici et, al. 2004; Vanegas and Tortorici 2002). rogorc zemoT iyo naCvenebi, par-Si da rvm-Si araopioiduri, ara-steroiduli anTebis sawinaaRmdego wamlebis mikroineqcia iwvevs antinocicefcias tolerantobis efeqtTan erTad (Jones 1996;. Pernia-Andrade et al.2004;. Tortorici et al. 2009; Tortorici et al. 2004; Tortorici at al. 2000; Tortorici and Vanegas 2000). naCvenebia, rom dipironis (metamizolis) mikroineqcia nakeris did birTvSi, pentobarbitaliT msubuqad anesTezirebul virTagvebSi, iwvevs doza damokidebul tail-flick refleqsis Sekavebas ( Jones 1996). dipironis da lizin-acetil salicilatis ganmeorebiTi mikroineqcia par-Si, opioiduri wamlebis msgavsad, iwvevs tolerantobas withdrawal-is sindromTan erTad (Pernia-Andrade at al. 2004; Tortorici at al. 2000; Tortorici and Vanegas 2000) da par-Si dipironis mikroineqciiT aRZruli antinocicepturi efeqti naloqsonis gavleniT reversias ganicdis (Hernandez and Vanegas,2001; Tortorici et al, 1996; Vasquez and Venegas, 2002). Cveni kvlevebiTac naCvenebia asasw-ebis ganmeorebiTi intraperitoniuli, amigdalas centralur birTvSi da par-is ventro-lateralur nawilSi mikroineqciebiT gamowveuli tolerantobis efeqti (Tsagareli at al. 2005; Tsiklauri at al.. 2006; Tsiklauri at al. 2008; Tsiklauri at al. 2009; Tsiklauri and Tsagareli 2006; Tsiklauri at al. 2010). erTad aRebuli es Sedegebi miuTiTebs, rom ara-opioiduri arasteroiduli anTebis sawinaaRmdego wamlebi analgezias axorcieleben endogenuri

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opioiderguli meqanizmebis gaaqtivebiT (Henricher and Ingram 2009; . Hernández-Delgadillo and Cruz 2006) . kvlevis am nawilSi SeviswavleT analginis, qsefokamis, ketorolakis da klodifenis mikroineqciebiT nakeris did birTvsa da rvm-Si gamowveuli tolerantoba mamr virTagvebSi. virTagvebSi asasw-ebis mikroineqcia nakeris did birTvSi iwvevs antinocicefcias, rac gamoixateba tail flick da hot plate latentobis gazrdiT fiziologiuri xsnariT igive ubanSi mikroineqcirebuli virTagvebis jgufTan SedarebiT. tail flick latentoba sarwmunod izrdeba da analginisTvis [ANOVA:F(5,44)=53.797, (P<0.0001)], klodifenisTvis [ANOVA:F(5,39)=43.233, (p<0.0001)], ketorolakisTvis [ANOVA:F(5,44)=39.952, (P<0.0001)], da qsefokamisTvis [ANOVA:F(5,39)=41.904, (P<0.0001)] (sur 24 A). aseve sarwmunod izrdeba hot plate latentoba da analginisTvis [ANOVA:F(5,44)=79.984, (P<0.0001)], klodifenisTvis [ANOVA:F(5,39)=33.024, (P<0.0001)], ketorolakisTvis [ANOVA:F(5,44)=68.839, (P<0.0001)], da qsefokamisTvis [ANOVA:F(5,39)=67.945, (p<0.0001)] Sesabamisad (sur 24 B). asasw-ebis ganmeorebiTi Seyvanis Semdeg xdeba antinocicefciis daqveiTeba, ise rom meoTxe dRes mTlianad moxsnilia analgeziuri efeqti rogorc tail flick ise hot plate (sur24 A, B) testSi yvela wamlisTvis analginis garda, am ukanasknelSi ar aris naCvenebi tolerantoba mexuTe dResac ki, (sur 24 A, B) virTagvebis calke jgufis rvm-Si mikroineqciebis fonze gamoicada µ-opioiduri antagonisti naloqsonis mimarT,. eqsperimentis pirvel dRes rvm-Si asasw-is mikroineqciidan erTi saaTis Semdeg, vaxdendiT naloqsonis mikroineqcias, romelic mTlianad xsnida asasw-iT gamowveul analgezias, rogorc tail flick (sur 25) ise hot plate (sur 26P) testSi, meore dRes asasw-is mikroineqcia qsefokamis, ketorolakis da klodifenis ineqciis Semdeg iwvevs mcired gazrdil antinocicefcias qsefokamis da ketorolakisTvis HP testSi, da mxolod qsefokamisTvis TF testSi, analginis da klodifenis testSi ki analgeziis maCvenebeli TiTqmis Tanxvedrilia naloqsonis mikroineqciis Semdgom latenturi periodis. miRebuli SedegebiG miuTiTebs, rom opioduri antagonisti naloqsoni aseve antagonisturad moqmedebs ara-opioidur analgetikebze da blokavs asasw-ebiT gamowveul analgezias rvm-Si, rac kidev erTxel adasturebs, rom ara-opioidur analgeziaSi monawileoben endogenuri opioidebi (Heinricher et,al.2009;. Tortorici et,al.2004; Tsiklauri et,al.2010). am kvleviT pirvelad aris naCvenebi Aasasw-is mikroneqciiT gamowveuli tolerantoba nakeris did birTvSi da rvm-Si naloqsoniT asasw-ebis antinocicepturi efeqtis dablokva, rac adasturebs sxva mkvlevarebis Sedegebs rom µ-opioiduri antagonistis naloqsonis da CTOP (D-phe-Cys-Tyr-D-trp-Orn-thr-Pen-thr-NH2) sistemuri Seyvana an mikroineqcia blokavs dipironiT da lasa-Ti gamowveul antinocicefcias (Heinricher et, al. 2009, Pernia-Andrade et, al 2004; Tortorici et, al,2009). Tu ra meqanizmiT axorcieleben asasw-ebi endogenuri opioidebis CarTvas par-Si bolomde garkveuli ar aris. gama-amino-erbos (gaem) mJavas Semcveli sinafsebi aris erT-erTi SesaZlo ubani, sadac asasw-ebs SeuZliaT endogenur opioidebTan konvergencia. Ppar-is gamosavlis neironebi, romlebic antinocicefciaSi CarTulni arian daRmavali gzebiT, ndb-s da rvm-is gavliT, kavdebian gaemerguli sinafebiT (Henricher and Ingram 2009).

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endogenuri opioidebi iwveven gaem-is presinaptikur gamonTavisuflebas par-Si, kerZod µopioiduri receptorebis aqtivacias, rasac moyveba araqidonis mJavis metabolitebis ujredSida koncentraciis gazrda. erTerTi gziT xdeba hepoqsolinis formireba, romelic zrdis kaliumis ganvladobas. Ees iwvevs presinaptikuri gaemerguli terminalebis hiperpolarizacias da gaem-is gamoTavisuflebas (Vaugan1998). par-is gamosavlis neironebis ganSekaveba iwvevs antinocicefciis daRmavali gzebis CarTvas da tkivilis Sekavebas zurgis tvinis doneze ( Morgan 2008, . Wessendorf et, al, 2006.). rogorc Cans am gzebis gaaqtivebisTvis aucilebelia µopioiduri receptorebi, vinaidan naloqsoni da CTOP blokavs par-Si mikroineqcirebuli asasw-ebis efeqts. (Pernia-Andrade et, al, 2004,Tortorici et, al.., 2009).

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A

***

0

2

4

6

8

1dRe 2 dRe

latentoba wm.

ketorolaki

naloqsoni

A

***

0

2

4

6

8

1 dRe 2dRe

latentoba wm.

klodifeni

naloqsoni

A

***

sur. 25 rvm-Si asasw-ebisP mikroineqciiT gamowveuli tail flick refleqsis latenturi periodis cvlileba

75

0

2

4

6

8

10

12

14

1 dRe 2 dRe

lat

entoba

wm.

qsefokami

naloqsoni

A

***

**

0

2

4

6

8

10

12

14

1 dRe 2 dRe

latentoba wm

analgini

naloqsoni

***

**

B

0

2

4

6

8

1dRe 2 dRe

latentoba wm.

ketorolaki

naloqsoni

A

***

0

2

4

6

8

10

12

14

1 dRe 2dRe

latentoba wm.

klodifeni

naloqsoni*

B

sur. 26 rvm-Si asasw-ebis mikroineqciiT gamowveuli hot plate refleqsis latenturi periodis cvlileba

76

sur 27. nakeris did birTvSi asasw-ebis mikroineqciis ubnebi Paxinos & Watson-is atlasis mixedviT. Distancia bregmadan-9.2mm (A) -9.5(B) da - -5.8mm (C) Sesabamisad.

77

gansja warmodgenili masalis safuZvelze, SeiZleba davaskvnaT, rom araopioidebis ganmeorebiTi Seyvana, opioidebis ganmeorebiTi ineqciebis msgavs efeqts iZleva: orive SemTxvevaSi viTardeba tolerantoba. araopioiduri tkivilgamayuCebeli wamlebis analgeziuri efeqtebi nawilobriv gamowveuli unda iyos centraluri nervuli sistemis struqturebze maTi zemoqmedebiT. asasw - ketorolaki, metamizoli (analgini), lizin-acetil-salicilati (lasa) da qsefokami, – rogorc sistemuri Seyvanis pirobebSi, aseve maTi mikroineqciebi cns-is tkivilis endogenuri modulaciis struqturebSi aaqtivebs tkivilis daRmaval makotrolebel sistemas da akavebs zurgis tvinis nociceptur refleqsebs. periaqueduqtis ruxi nivTiereba maRali koncentraciiT Seicavs samive tipis

µ, δ, da κ-opioidur receptorebs da mdidaria endogenuri opioidebiT, rogorebicaa enkafalini, endorfini, dinorfini (Dickenson and Kieffer 2006, Dray 2009, Zubieta 2009)

ventrolateralur par-Si enkefalin Semcveli sinafsuri kavSirebi nanaxia par–rvm-is, rogorc gaem, ise ara-gaem Semcveli neironebis dendritebze (sur 28 ). endogenuri opioidebis gaaqtiveba iwvevs par-is gaem-erguli neironebis Sekavebas da Sesabamisad maTi samizne neironebis ganSekavebas, rac ganapirobebs antinocicefcias (Christie at al 2000), kerZod,Ppostsinafsuri µ-opioiduri receptorebis gaaqtiveba endogenuri, Tu egzogenuri opioidebiT, aaqtivebs G-cilasTan-SeuRlebul potencial-damokidebul kaliumis arxebs, an araqidonis mJava/fosfolipazaA2 meorad mesenjerul gzebs. Sedegad kaliumi gamodis terminalebidan, adgili aqvs terminalebis hiperpolarizacias da potencial-damokidebuli kalciumis arxebis daxurvas. Sesabamisad mcirdeba gaem-is gamoTavisufleba ventro-lateraluri par-is neironebze da Sedegad irTveba tkivilis daRmavali kontrolis sistema da xdeba am daRmavali antinocicepturi gzebis aqtivacia (sur 29, 30) (Christie, et al., 1999; 2000; Hack et al, 2003, Heinricher, Ingram, 2009). zogierTi avtori gamoTqvams mosazrebas, rom par-Si araopioiduri analgetikebi endogenuri opioidebis sinergistulad unda moqmedebdnen; isini neironebSi unda iwvevdnen oqsigenazebis blokirebas (sur. 29,30), Sedegad producirdeba didi raodenobiT araqidonis mJava 12-lipo-oqsigenazuri sistemiT da Sesabamisad mcirdeba gaem-is gamoyofa da aqtivdeba tkivilis daRmavali kontrolis sistema. Tumca iwveven Tu ara par-Si metamizolisa da sxva asasw-ebis mikroineqciebi ciklo-oqsigenazuri aqtivobis Sekavebas jer kidev dasazustebelia. miuxedavad amisa, radgan endogenuri analgeziuri sistemis struqturebSi asasw-s mikroineqciis efeqtebs amcirebs imave ubanSi naloqsonis mikroineqcia, unda vifiqroT, rom es faqti ukavSirdeba adgilobriv (lokalur) endogenur opioidebs (Tortorici, Vanegas, 2000; Heinricher, Ingram, 2009).

Cveni monacemebi eTanxmeba centraluri nervuli sistemis supraspinalur struqturebSi tkivilis mgrZnobelobis regulaciis meqanizmis Sesaxeb arsebul Sexedulebas, romlis Tanaxmad, am procesSi mTavar rols unda asrulebdes endogenuri opioiduri sistema. modulatorul funqcias opioidebi da SesaZloa asasw asruleben

78

presinafsur doneze, axdenen ra neirotransmiterebis gamoTavisuflebis inhibirebas nocicepturi sistemis sinafsebSi (Tortorici, Vanegas, 2000; Heinricher, Ingram, 2009).

sur. 28 opioidebis aqtivobis ujreduli meqanizmi par-Si (Heinricher, Ingram, 2009).

79

sur. 29 opioidebisa da asasw-s interaqtivobis meqanizmi cns-is neironul terminalebSi. (Christie et al, 1999)

80

sur.30 asasw-s da opioidebis mier gaem-is dablokvis meqanizmi. ( Heinricher, Ingram, 2009).

81

Tavi 4. daskvnebi 1. araopioiduri tkivilgamayuCebeli wamlebis analgeziuri efeqtebi nawilobriv gamowveulia maTi moqmedebiT centraluri nervuli sistemis (cns) struqturebze. 2. asasw, rogorebicaa ketorolaki, metamizoli (analgini), lizin-acetil- salicilati (lasa) da qsefokami, sistemuri Seyvanis pirobebSi, aaqtiveben tkivilis daRmaval makotrolebel sistemas, da amdenad akaveben zurgis tvinis nociceptur refleqsebs. 3 metamizolisa da ketorolakis da qsefokamis intraperitonealuri (i.p) ineqciiT gamowveuli Sekaveba xorcieldeba daRmavali endogenuri opioiderguli wris CarTviT, radganac es efeqti iblokeba naloqsonis sistemuri SeyvaniT. 4 metamizolis, ketorolakisa da qsefokamis ganmeorebiT i.p. ineqciebs mivyavarT antinocicepturi Zalis progresul Semcirebamde, rac gamoixateba tolerantobaSi maT mimarT da kros-tolerantobaSi morfinis i.p. ineqciis mimarT. 5 axalgazrda da zrdasruli asakis virTagvebSi tolerantoba sxvadasxva dinamikiT viTardeba. Aaxalgazrda cxovelebSi es movlena viTardeba ufro swrafad da eqsperimentis bolo dRes isini hiperalgeziurebi xdebian. rogorc axalgazrda, ise zrdasruli morfin-tolerantuli virTagvebi krostolerantobas avlenen asasw-ebis mimarT 6 amigdalas centralur birTvSi asasw-ebis uni- da bilateraluri ganmeorebiTi mikroineqciebi iwveven tolerantobas maT MmimarT da krostolerantobas morfinis mimarT. 7 periaqueduqtis ruxi nivTierebis ventro lateralur nawilSi asasw-ebis A ganmeorebiTi mikroineqciebis Sedegad viTardeba tolerantoba maT MmimarT. 8 nakeris did birTvSi asasw-ebis ganmeorebiTi mikroineqciebi iwveven tolerantobas 9 mogrZo tvinis rostro ventralur midamoSi asasw-ebis analgeziuri efeqti iblokeba opioiduri antagonisti naloqsoniT.

82

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1. Tsiklauri N., Viatchenko-Karpinski V., Voitenko N., Tsagareli M.G. Non-opioid tolerance in juvenile and adult rats. European J. Pharmacol., 2010, Vol. 629, Nos. 1-3, pp. 68-72.

2. Klein A.H., Sawyer C.M., Iodi Carstens M., Tsagareli M.G., Tsiklauri N., Carstens E. Topical

application of L-menthol induces heat analgesia, and a biphasic effect on cold sensitivity in rats. Behav. Brain Research., 2010, Vol. 212, No.2, pp. 179-186.

3. Tsagareli M.G., Tsiklauri N., Zanotto K.L., Iodi Carstens M., Klein A.H., Gurtskaia G., Sawyer C.M., Abzianidze E., Carstens E. Behavioral evidence of heat hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats. Neurosci. Letters, 2010, Vol. 473, No.3, pp. 233-236. 4. Tsiklauri N, Nozadze I, Gurtskaia G, Berishvili V, Abzianidze E, Tsagareli M.G. Tolerance

induced by non-opioid analgesic microinjections into rat's periaqueductal gray and nucleus raphe. Georgian Med. News,2010, Vol. 17, No. 3(180), pp. 47-55.

5. Tsagareli M.G., Tsiklauri N., Gurtskaia G., Nozadze I., Kandelaki R., Abzianidze E. The central nucleus of amygdala is involved in tolerance to the antinociceptive effect of NSAIDs. Inter. J. Health, 2010, Vol.2, No.1, pp. 64-68. 6. Tsagareli M.G., Tsiklauri N., Gurtskaia G., Nozadze I., Kandelaki R., Abzianidze E. Tolerance

effects induced by NSAIDs microinjections into the central nucleus of the amygdala in rats. Neurophysiology, 2009, Vol. 41, No.6, pp. 404-408.

7. Tsiklauri N., Nozadze I., Gurtskaia G., Kandelaki R., Abzianidze E. Tsagareli M.G. Evidence for tolerance effects induced by non-opioid analgesics microinjected into the central nucleus of amygdala in the rat hot plate test. Bull. Georgian National Acad. Sci., 2009, New Series, Vol. 3, No. 2, pp. 141-146. [www.science.org.ge] 8. Цагарели М.Г., Циклаури Н.Д., Гурцкая Г.П., Нозадзе И.Р., Канделаки Р.А,

Абзианидзе Е.В. Эффекты толерантности, индуцированные микроиньекциями нестероидных противо-воспалительных агентов в центральное ядро амигдалы крыс. Нейрофизиология, 2009, т. 41, № 6, с. 476-482.

9. Tsiklauri N., Nozadze I., Gurtskaia G., Abzianidze E. Tsagareli M.G. Tolerance induced by non-opioid analgesic microinjections into the central nucleus of amygdala of rats. Bull. Georgian National Acad. Sci., 2008, New Series, Vol. 2, No.3, pp. 129-133 [www.science.org.ge]

10. Tsiklauri N., Gurtskaia G., Tsagareli M.G. Study of non-opioid analgesic tolerance in young and adult rats. Georgian Med News, 2008, No 5(158), pp. 40-44. 11. Tsiklauri N., Tsagareli M.G. Non-opioid-induced tolerance in rats. Neurophysiology, 2006,

Vol. 38, No.4, pp.370-373.

12. Tsiklauri N., Tsagareli M.G. Study of xefocam antinociception in rats. Bull. Georgian Acad.. Sci., 2006, Vol.174, No.3, pp. 496-499. [www.science.org.ge]

13. Tsiklauri N., Gurtskaia G., Tsagareli M.G. Is endogenous opioid system involved in non-

opioid analgesics tolerance? Georgian Med News, 2006, No. 8(137), pp. 121-125 14. Tsagareli M.G., Tsiklauri N., Lagidze T., Gurtskaia G., Berishvili V., Abzianidze E., Tolerance induction by non-opioid analgesics in rats. Proc. Georgian Acad. Sci. Biol. Series A, 2005,

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Vol.31, No.6, pp. 903-909.

15. Tsiklauri N., Kiteishvili D., Tsagareli M.G. Examination of ketorolac antinociception in Rats. Bull.Georgian Acad. Sci.,2005, Vol.172, No.3, pp. 534-536. [www.science.org.ge]

16. Tsiklauri N., Lagidze T., Gurtskaia G., Berishvili V., Abzianidze E., Tsagareli M.G. Investigation of analgine (metamizol) tolerance in rats. Proc. Georgian Acad. Sci., Biol.Series A, 2005, Vol.31, No.4, pp.607-611.

17 Tsiklauri N., Tsagareli M.G. Study of analgine (metamizol) antinociceptive action in rats. Bull. Georgian Acad. Sci.,2005, Vol.171, No.3, pp. 530-532.