opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain

8/11/2019 Opioid and Noradrenergic Contributions of Tapentadol in Experimental Neuropathic Pain

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Neuroscience Letters 562 (2014) 9196

Contents lists available at ScienceDirect

Neuroscience Letters

j ournal homepage: www.elsevier .com/ locate /neulet

Plenary article

Opioid and noradrenergic contributions oftapentadol in experimental

neuropathic pain

Diana S. Meske,Jennifer Y. Xie,Janice Oyarzo, Hamid Badghisi,Michael H. Ossipov, Frank Porreca

Department of Pharmacology, University of Arizona HealthSciences Center, Tucson, AZ 85724, USA

h i g h l i g h t s

Systemic tapentadol or duloxetine increases spinal norepinephrine levels. Tapentadol shows greater activity in nerve-injured rats relative to sham-operated rats. Systemic morphine reduces spinal norepinephrine levels.

a r t i c l e i n f o

Article history:

Received 2 July 2013

Received in revised form 6 August 2013

Accepted8 August 2013

Keywords:

Tapentadol

Spinal norepinephrine

Opioid

NoradrenergicNorepinephrine reuptake inhibition

a b s t r a c t

Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake block-

ing activity that has recently been introduced for the treatment ofmoderate to severe pain. The effects

of intraperitoneal (i.p.) morphine (10mg/kg), tapentadol (10 or 30mg/kg) or duloxetine (30mg/kg), a

norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats

with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects ofthese drugs on spinal cere-

brospinal fluid (CSF) NE levels were quantified. Response thresholds to von Frey filament stimulation

decreased significantly from baseline in SNL, but not sham, operated rats. Duloxetine, tapentadol and

morphine produced significant and time-related reversal of tactile hypersensitivity. Duloxetine signif-

icantly increased spinal CSF NE levels in both sham and SNL rats and no significant differences wereobserved in these groups. Tapentadol (10mg/kg) produced a significant increase in spinal NE levels in

SNL, but not in sham, rats. At the higher dose (30mg/kg), tapentadol produced a significant increase

in spinal CSF NE levels in both SNLand sham groups; however, spinal NE levels were elevated for an

extended period in the SNLrats. This could be detected 30min following tapentadol (30mg/kg) in both

sham and SNLgroups. Surprisingly, while the dose ofmorphine studied reversed tactile hypersensitivity

in nerve-injuredrats, CSF NE levels were significantly reduced in both sham- and SNLrats. The data sug-

gestthat tapentadolelicits enhancedelevation in spinal NE levels in amodelofexperimentalneuropathic

pain offering a mechanistic correlate to observed clinical efficacy in this pain state.

2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Pain is a complex experiencewith sensory, emotional and cog-

nitive components [25]. The context in which nociceptors areactivated plays an important role in the experience of pain [3,4].

Imaging studies performedwith human volunteers receiving nox-

ious stimuli under different experimental conditions have shown

activation of brain areas known to process emotional responses,

mood and attention [4,39]. Contextual engagement of multiple

brain regions appear to participate in a top-down modulation

of nociceptive circuits resulting in facilitation or inhibition of

Corresponding author. Tel.: +1 520 6267421.

E-mail address: [email protected] (D.S. Meske).

nociceptive inputs at the level of the spinal and trigeminal dorsal

horn to elicit the pain experience [28].

The rostral ventromedialmedulla (RVM) forms a final common

relay in thedescendingmodulationof nociception inputs[14]. Thisregion has reciprocal connections with the periaqueductal gray

(PAG) and together these loci form a key nexus of pain modula-

tion [14]. These regions also have reciprocal connections with the

locuscoeruleus(A6)andtheKollikerFusenucleus (A7),makingup

the pontine nuclei that are themainsourceofNEprojections tothe

spinal cord [17,37,46]. Descending inhibition is believed to result,

in part, from release of spinal NE [14,21,32,38]. Early animal stud-

ies had shown that the antinociceptive effect of supraspinal, but

notspinal,morphinedepends onactivation ofspinal2-adrenergicreceptors suggesting an important role of descending noradren-

ergic projections [45]. Accordingly, the antinociceptive effect of

0304-3940/$ seefrontmatter 2013 Elsevier Ireland Ltd. All rightsreserved.

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92 D.S. Meske et al. / Neuroscience Letters 562 (2014) 9196

opioids are blocked by systemic or spinal administration of2-adrenergic antagonists and enhanced by 2-adrenergic agonists[26,29,31,44,45]. We, andothers, have shown that theendogenous

noradrenergic inhibitory systemmay protect against the develop-

ment of signs of neuropathic pain in nerve-injured rats suggesting

an important role of descending inhibition in chronic pain states

[11,19,43]. Additionally, numerous pharmacological studies have

demonstrated antinociceptive synergy between -opioid and2-adrenergic agonists at the spinal level [29,30].

Tapentadol was developed to mechanistically exploit the pos-

itive interaction between the opioid and the spinal NE system

[34]. This compound exhibitsweak affinity (i.e. 50-fold lower than

morphine) at the -opioid receptor but additionally produces NEreuptake inhibition that is hypothesized to produce a synergis-

tic-opioid/2-adrenergicmechanistic interactionwithenhancedanalgesic effects, particularly in neuropathic pain states [34].

As noted above, the antinociceptive effects of systemic and

supraspinal morphine are blocked by spinal2-adrenergic recep-tor antagonists suggesting the release of spinal NE. However, few

studieshavemeasuredspinalNE levels followingmorphineadmin-

istrationdirectly [5]. A recent studyshowedthatmorphine slightly

reduced, rather than enhanced, spinal NE in the nave rat [40].

In the present investigation, we compared the ability of

tapentadol and morphine to reverse nerve-injury induced tactile

hypersensitivity andtomodulatespinalNE inratswith experimen-

tal neuropathic pain or in sham-operated controls. Duloxetine, a

dual NE/5HT reuptake blocker was also studied for comparison.

2. Methods

2.1. Animals

Male,Sprague-Dawleyrats (HarlanLaboratories Inc.,Indianapo-

lis, IN, USA)weighing300325g at the timeof testingwerehoused

in a climate-controlled room on a 12h light/dark cycle. Food and

water were available at all times ad libitum. All experiments were

performed in accordance to policies and procedures set forth by

theInternational Association for theStudyof Pain andtheNationalInstitutes of Health guidelines for the handling and use of labora-

tory animals. Approvalwasobtained from the Institutional Animal

Care and Use Committee of the University of Arizona prior to all

experimentation. Every effort was made to minimize animal pain

and distress as well as to minimize the number of animals used.

Experimenters were blinded to the treatment group in all behav-

ioral experiments.

2.2. Spinal nerve ligation

As previously described by Kim and Chung, the L5/L6 surgical

procedurewas used to produce experimental chronic neuropathic

pain [22]. Rats were anesthetized with isoflurane (2% mixed with

room air; 2L/min) and the lumbar vertebrae were exposed. TheL5 and L6 spinal nerveswere identified and tightly ligated with 4-

O silk suture and the wound was closed. Sham-operated ratswere

preparedin thesamemanner asthe SNLratsexcept theL5/L6 spinal

nerves were not ligated. All rats were monitored for any visual

signs of motor deficits, as well as for general health and weight

maintenance.

2.3. CSF collection catheter preparation

The day before the surgery, 2 in. segments of PE-60 tubing (Sci-

entific Commodities Inc., Lake Havasu, AZ, USA) were cut. Needle

tips were removed from 23Gsyringes (BDPrecisionGlide, Franklin

Lakes, NJ, USA). Using super glue, syringe needle, PE-60 tubing,

and a gel loading pipette tip (Fisher Scientific, Pittsburgh, PA,USA)

were securely fastened together to form a catheter. Catheterswere

allowed todry overnight.On the day of the collectiona P200Pipet-

teman (Rainin, Columbus, OH, USA) was used with the prepared

catheter to collect CSF.

2.4. Drug administration

The animals received an intraperitoneal (i.p.) injection of mor-

phine (10mg/kg) or tapentadol (10 and 30mg/kg) dissolved insterile saline or duloxetine (30mg/kg) in distilled H2O. Normal

saline was used as the vehicle. Duloxetine was purchased from

ChemPacificCorporation (Baltimore,MD,USA),morphinewaspro-

vided by the NIDA Drug Supply Program and tapentadol was

provided by Grunenthal Gmbh (Aachen, Germany).

2.5. Tactile hypersensitivity

Tactilewithdrawalthresholdsweredetermined1014daysfol-

lowing sham or SNL surgery. The rats were placed in suspended

plastic chamberswith wire mesh bottoms for0.5h prior to testing.

A seriesof calibrated vonFrey filamentswasappliedperpendicular

to the plantar aspect of the ipsilateral hindpaw until the filament

buckled [8,12,23]. Theup-downmethodwasused todeterminethe50% withdrawal threshold with the Dixon nonparametric test as

previously described [8,12,23]. Behavioral testing was performed

approximately 10min prior to initiation of CSF collection (i.e.; 20,

50 and 80min after injection).

2.6. CSF collection

CSF was collected from nave animals, or following sham- or

SNLsurgery.Ratswereanesthetizedwith isoflurane(2%mixedwith

room air, 2 L/min)andplaced ina stereotaxic frame.A 1.5cm longi-

tudinal incisionfromthebackridgeofthe skull toC1wasmadeand

the muscles were retracted to expose the atlanto-occipital mem-

brane. A prepared catheter andmicropipettewasused to puncture

the membrane and collect the CSF (70150l), free of blood, fromthe cisterna magna. The CSF was combined with an antioxidant

cocktail (6.0mM 1-cysteine, 2.0mM oxalic acid, and 1.3% glacial

acetic acid) and kept on ice in order to prevent the breakdown of

catecholamines[18]. Thesampleswerecentrifuged(14,000rpm)at

4 Cfor5min. Theamountof CSFcollectedwasmeasuredandadded

to a single catecholamine extraction tube. Catecholamine extrac-

tion kitswere purchasedfromESA, Inc., (Chelmsford,MA,USA) and

the protocolwas followed in full as per the providedmanual.

2.7. HPLC with EC detector analysis

The HPLC system consisted of an Agilent 1100 quanternary

pump and thermostated autosampler (Agilent Technologies, Palo

Alto, CA, USA) coupled to an in-line Coulochem III electrochemi-cal detector with model 5011Aanalytical cell (E1150mV and E2

+250mV) andmodel 5020guard cell (+350mV) (ESA Inc., Chelms-

ford, MA, USA). Using MD-TM mobile phase, at a flow rate of

0.400ml/min, catecholamines were separated in samples using

a MD-150 analytical column (3mm15cm) (ESA Inc., Chelms-

ford,MA,USA).Agilent ChemStation dataacquisition softwarewas

used to analyze the chromatograms (Supplemental Fig. 1). Each

sampleof CSF was thenspikedwith a known amount ofNEand re-

injected into the HPLC system. The chromatograms were overlaid

to confirm that the correct peak, indicated by a retention time of

approximately 2.6min, was collected. Additionally, a minimum of

3 separate seriesof sequentiallyvarying amounts ofNE in artificial

CSF (aCSF) was injected into the HPLC system in order to generate

a standard curve (y=0.8588x+1.203, r2

=0.9998). The lower limit


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D.S. Meske et al. / Neuroscience Letters 562(2014) 9196 93

of detection (LOD; 0.5 pg) and lower limit of quantification (LOQ;

1.5pg) were determined.

Supplementary material related to this article can be found,

in the online version, at http://dx.doi.org/10.1016/j.neulet.2013.

08.017.

2.8. Statistical analysis

Evoked pain behaviors were analyzed for significant changesfrom baseline (presurgery) control valueswith one-factor ANOVA

followedbytheposthocDunnett test. SpinalNElevelsare expressed

as the % of the mean spinal NE concentration obtained from nave

animals (0.820.08pg/l;N=42). Significant changes inNE levelsfrom nave, representing 100%,were determined with ANOVA fol-

lowed by the post hocDunnett test. All evaluations were obtained

using GraphPad Prism 5.00 forWindows (GraphpadSoftware, San

Diego, CA,USA; http://www.graphpad.com).

3. Results

3.1. Reversal of tactile hypersensitivity in rats with SNL

Tactile hypersensitivity was measured in animals 1014 daysfollowing sham- or SNL surgery (i.e., baseline) and again at 20

and 50min after drug injection. These time points were approx-

imately 10min prior to collection of CSF (i.e., at 30 and 60min

post-injection). SNL, butnotsham, surgery produced tactile hyper-

sensitivity that was significantly (p


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Baseline SNL 50 80

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Sham-operated

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Fig. 2. Rats with sham surgery or SNL received either 30mg/kg, i.p. (A) or 10mg/kg, i.p. (B) of tapentadol. Both doses of tapentadol produced a full reversal of tactile

hypersensitivity in SNL rats, indicated by the significant (p


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