(665) Cannabinoid agonist WIN55,212-2 suppresses opioid-induced pruritus in mice

H Lee, M Ko, S Oh, K Shin; Korea University, College of Medicine, Seoul, KoreaCannabinoid receptor agonists receptor can reversed opioid-inducednausea, vomiting in animals but have not been tested against opioid-induced pruritus yet. This study tests the hypothesis that cannabinoidreceptor agonist will prevent opioid-induced pruritus and also tests thatcannabinoid receptor agonist will increase the analgesic efficacy of opi-oids in that dose range. Male ICR mice, 20-25 g, were used. All drugswere injected subcutaneously. For getting the dose-response curve offentanyl by writhing test, acetic acid (0.6%, 0.4 ml, i.p.) was injected 5minute prior to 10 minute observation period. Various doses of fentanyl(vehicle, 0.001, 0.0032, 0.01, 0.032, 0.1 mg/kg, 10 ml/kg) were pretreated15 min earlier. To observe analgesic potentiation of WIN55,212-2 inwrithing test, various concentration of WIN55,212-2 (0.25, 0.5, 1.0, 2.0mg/kg, 10 min PT) were pretreated 10 minutes earlier than the injectionof ED50 dose of fentanyl from previous dose-response curve. To observeantipruritogenic effect of WIN55,212-2 in scratching test, various doseof WIN55,212-2 (0.25, 0.5 mg/kg) were pretreated 20 minutes earlierthan fentanyl injection. AM251 (3 mg/kg) was used to confirm receptorselectivity. The ED50 of fentanyl in writhing test was 0.018 (0.011-0.025)mg/kg. WIN55,212-2, 1 mg/kg, can increase the analgesic efficacy offentanyl significantly (p � 0.01) but not 0.25, 0.5 mg/kg. WIN55,212-5,0.25 mg/kg can reduce the scratching responses of fentanyl significantly(p � 0.01) and these were receptor selective. These results demonstratethat WIN55,212-2, 0.25 mg/kg, can prevents opioid-induced pruritus andthe antipruritogenic activity of WIN55,212-2 occurs at CB1 receptorseven if analgesic efficacy of fentanyl cannot be increased in that dose.

(666) Bicifadine: Characterization of its molecular pharmacol-ogy and efficacy in animal models of acute pain

E Koustova, A Basile, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hacken-sack, NJBicifadine (DOV 220,075) is a balanced inhibitor of norepinephrine andserotonin uptake (IC50 � 553, 11726 nM, respectively) which exhibitsno significant affinity for �, �, and � opioid receptor subtypes as well asa host of other receptors/ion channels/enzymes, including the NMDA,nicotinic and muscarinic cholinergic, vanilloid, orphanin, NK and canna-binoid receptors, voltage-gated sodium, potassium and N-type calciumchannels, and COX1, COX2. This profile suggests that the primary molec-ular mechanism responsible for analgesic actions of bicifadine relates toits ability to modulate monoaminergic neurotransmitter pathways. Bici-fadine is an effective analgesic in 2 models of yeast-induced plantarinflammation (Randall-Selitto and Atkinson-Cowan tests, ED50 � 9.2,17.9 mg/kg PO) while showing activity in the tail-flick nociception test. Itis also an effective reducing the phenylquinone writhing response(ED50 � 13 mg/kg PO). In the formalin test, bicifadine significantly de-creases the paw licking time in both the early and late phases (MED � 10mg/kg PO). Repeated (5 days) administration of bicifadine (50 mg/kg,PO) did not reduce its analgesic activity in the Randall-Selitto test. Thereis no evidence of motor activation or stereotypies following acute ad-ministration, or the development of dependency following 48 days ofbicifadine administration. In conclusion, bicifadine is a potent and ef-fective oral analgesic in a variety of models of acute inflammatory painand nociception. Moreover, there is no evidence of the development oftolerance or abuse liability associated with bicifadine administration.

(667) Bicifadine is an efficacious analgesic in animal models ofneuropathic pain

A Basile, E Koustova, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hacken-sack, NJBicifadine (DOV 220,075), a balanced inhibitor of norepinephrine andserotonin uptake, was evaluated in two models of neuropathic pain:streptozotocin-induced diabetic neuropathy, and the spinal nerve liga-tion (SNL) model (Kim and Chung, 1992). In the diabetic neuropathymodel, the effect of bicifadine on the paw pressure withdrawal thresh-old was determined using the Randall-Selitto test. Bicifadine’s efficacy inreducing mechanical allodynia in the SNL model was measured usingSemmes-Weinstein filaments and its effects on mechanical and thermalhyperalgesia were evaluated with the Randall-Selitto test and a focusedbeam of infrared radiation, respectively. Bicifadine dose-dependentlyreduced the nociceptive threshold for paw withdrawal in diabetic rats(ED50 � 5 mg/kg PO). Similarly, bicifadine reduced mechanical allodyniain the SNL model, with a maximum anti-allodynic action observed at40mg/kg PO, an effect comparable in magnitude to 300 mg/kg PO ofgabapentin. In addition, bicifadine induced anti-mechanical (ED50 � 12mg/kg PO) and thermal (MED 12.5 mg/kg PO) hyperalgesic effects. Theeffect of bicifadine in blocking mechanical hyperalgesia in the SNLmodel reached a maximum at 60 minutes and remained significant up to120 minutes after administration. Its effects in blocking thermal hyper-algesia reached a maximum at 30 minutes and lasted up to 240 minutesafter administration. Chronic administration (50mg/kg/day, 5 days, PO)of bicifadine did not result in the development of analgesic tolerance,with efficacy in reducing mechanical hyperalgesia in SNL rats similar toacute bicifadine (50mg/kg). In contrast, repeated administration of mor-phine (128 mg/kg/D, 5 days, PO) resulted in a significant reduction inefficacy. In conclusion, bicifadine is a potent and efficacious analgesic intwo well-described models of neuropathic pain, and exhibits no abusepotential.

(668) Peripheral analgesic effect of ketamineS Song; Yeungnam University Hospital, Daegu, South KoreaKetamine, competitive non-NMDA antagonist, is used to treat postop-erative and neuropathic pain. However, systemically administered ket-amine has some adverse effects such as hallucination and/or hyperten-sion and tachycardia. Some investigators insist that NMDA antagonist iseffective when it is administered before rather than after surgical stim-uli. This study was performed to compare the analgesic effects of ket-amine by the timing and the route of administration in rat formalin test.Fifty rats were divided into five groups; control (saline injected), twosystemic (intraperitoneal injection of 0.25 mg/0.1 ml of ketamine 5 minbefore or after formalin injection; Pre-IP/Post-IP), and two peripheral(subcutaneous infiltration of 0.25 mg/0.1 ml of ketamine on right hindpaw in the same site of formalin injection 5 min before or after formalininjection; Pre-LO/Post-LO) groups. Under enflurane anesthesia, all ratswere received subcutaneous infiltration of 50 ug of 5% formalin ontheir right hind paw according to their allocated groups. The number offlinches was compared during 2 (20-60 min0 after formalin injection. Allfour ketamine groups were significantly less flinches than in control (P �0.01). There were no significant differences according to the timing ofadministration (Pre-IP vs. Post-IP, Pre-LO vs. Post-LO, respectively). Pre-Logroup was significantly less flinches than in two systemic groups (P �0.05). These data suggest that subcutaneous infiltration of ketamine haslocal analgesic effect and the timing of administration is not majorfactor in its peripheral analgesia.

S22 Abstracts