The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control

Due to the limitations of currently available analgesics, a number of novel alternatives are currently under investigation, including neuronal nicotinic acetylcholine receptor (nAChR) agonists. During the 1990s, the discovery of the antinociceptive properties of the potent nAChR agonist epibatidine in rodents sparked interest in the analgesic potential of this class of compounds. Although epibatidine also has several mechanism-related toxicities, the identification of considerable nAChR diversity suggested that the toxicities and therapeutic actions of the compound might be mediated by distinct receptor subtypes. Consistent with this view, a number of novel nAChR agonists with antinociceptive activity and improved safety profiles in preclinical models have now been identified, including A-85380, ABT-594, DBO-83, SIB-1663 and RJR-2403. Of these, ABT-594 is the most advanced and is currently in Phase II clinical evaluation. Nicotinically-mediated antinociception has been demonstrated in a variety of rodent pain models and is likely mediated by the activation of descending inhibitory pathways originating in the brainstem with the predominant high-affinity nicotine site in brain, the α4β2 subtype, playing a critical role. Thus, preclinical findings suggest that nAChR agonists have the potential to be highly efficacious treatments in a variety of pain states. However, clinical proof-of-principle studies will be required to determine if nAChR agonists are active in pathological pain.     

Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists

A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.     

Nicotinic acetylcholine receptor agonists: a potential new class of analgesics

Current analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), are largely refinements of approaches available for more than 100 years and have critical liabilities and limitations. A number of new molecular targets for analgesia have been proposed in recent years, including the neuronal nicotinic acetylcholine receptor (nAChR). Agonists at neuronal nAChRs have antinociceptive effects in a variety of preclinical pain models. Moreover, nicotine can decrease experimentally-induced pain in humans without disrupting normal tactile sensation. These data from both experimental animals and humans suggest that compounds targeting neuronal nAChRs may represent a new class of analgesic agents. In this paper, we provide brief overviews of the physiology of pain, the animal models used to assess potential analgesics preclinically, and the biology of nAChRs. We then provide a review of preclinical data on the antinociceptive effects of a variety of neuronal nAChR agonists and a discussion of potential mechanisms, including evidence that antinociception is mediated by activation of brainstem nuclei with descending inhibitory inputs to the spinal cord. An evaluation of the clinical potential of this approach must also consider potential side effects. Undesirable side effects of nicotine are well known, but as we will discuss in detail, these effects are not produced by all neuronal nAChR agonists and the existence of neuronal nAChR subtypes may provide a basis for separating therapeutic effects from toxicities.     

Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors

A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.     

The unusual nature of epibatidine responses at the alpha4beta2 nicotinic acetylcholine receptor

The identification of an equatorial frog toxin, epibatidine, as a potent non-morphinic analgesic, selective for neuronal nicotinic acetylcholine receptors, provoked a marked renewal in our understanding of pain and its mechanisms. In this work we have examined the effects of epibatidine at the major brain rat alpha4beta2 nicotinic acetylcholine receptor expressed in a cell line. Fast drug applications obtained with a modified liquid filament system were used for the analyses of the currents evoked by acetylcholine, nicotine and epibatidine. Characterized by a slow onset and offset, epibatidine responses were of smaller amplitude to those evoked by acetylcholine or nicotine. About a thousand times more sensitive to epibatidine than acetylcholine, the alpha4beta2 receptor also displayed a more pronounced apparent desensitization to this compound. Finally, overnight exposure to 1 nM epibatidine failed to produce the functional upregulation observed with nicotine. These data indicate that, at the rat alpha4beta2 receptor, epibatidine acts as a partial agonist causing a pronounced inhibition of agonist evoked currents at concentrations that do not activate the receptors.     

Modulators of nicotinic acetylcholine receptors as analgesics

The analgesic properties of nicotine have prompted attempts to develop compounds that specifically target nicotinic acetylcholine receptors (nAChRs) in the nervous system, with the beneficial effects of nicotine but without its side effects. Thus far, only nAChR agonists have been reported as being in development for pain, although nAChR antagonists could also have a potentially analgesic action. Various problems associated with the use of nAChR agonists as analgesics have been identified and measures suggested to overcome some of them. This review describes the nAChR agonists A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SIB-1663, of which ABT-366833, ABT-202 and ABT-894 are currently undergoing development as pain therapeutics. In vivo studies of the pathomechanism of neuropathic pain indicate that targeting alpha3beta4 does not have a specific action on neuropathic pain, and that alpha3beta4 ligands cause side effects. On the other hand, alpha4beta2 receptors are specific for neuropathic pain, and ligands that bind preferentially to these receptors both effectively relieve pain and do not cause many adverse effects. This is the basis of the difference between the action of tebanicline, which binds with greater specificity to alpha3beta4 receptors, and ABT-366833, which binds more specifically to alpha4beta2 receptors.     

Comparison of the effects of epibatidine and nicotine on the output of dopamine in the dorsal and ventral striatum of freely-moving rats

The effects of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine on the extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal (caudate-putamen) and the ventral striatum (nucleus accumbens) of freely-moving male Wistar rats were studied by in vivo microdialysis. In the dorsal striatum, epibatidine (3.0 microg/kg s.c.) significantly elevated the extracellular concentrations of DA, DOPAC and HVA. In contrast, epibatidine did not alter the extracellular DA concentration in the ventral striatum, but elevated significantly the concentration of DOPAC and also tended to elevate that of HVA. In parallel experiments, nicotine (0.5 mg/kg s.c.) significantly increased DA output in the ventral striatum whereas only a modest and non-significant increase of extracellular DA concentration was found in the dorsal striatum. Earlier studies have shown that the doses of epibatidine and nicotine used in the present study are about equieffective at least with respect to the analgesia-producing or hypothermic effects of the drugs. Comparison of the effects of epibatidine and nicotine suggests that the responses of the mesolimbic and nigrostriatal dopaminergic systems to the two nicotinic receptor agonists differ. Epibatidine, in contrast to nicotine, preferentially stimulates the nigrostriatal vs. the mesolimbic dopaminergic system. Therefore, novel nicotinic AChR ligands structurally related to epibatidine may have low abuse potential.     

Antinociceptive effects of the alkaloid epibatidine: Further studies on involvement of nicotinic receptors

Epibatidine is a potent analgetic agent with high affinity for nicotinic receptors. The antinociceptive effects of epibatidine are blocked by both competitive and noncompetitive nicotinic antagonists. The L-type calcium channel activator Bay K 8644 potentiates the antinociceptive effects of epibatidine, while nifedipine antagonizes the antinociceptive effects. Acute treatment with chlorisondamine leads to long-term blockade of the antinociceptive effects of epibatidine. The antinociceptive effects of epibatidine are reduced in mice rendered tolerant to the behavioral effects of nicotine by chronic nicotine or caffeine treatment. Epibatidine has very high affinity for the major central nicotinic receptor to which [³H]nicotine binds. However, unlike nicotine and cytisine, epibatidine is very potent at ganglionic-type nicotinic receptors. Epibatidine in cultured cells causes desensitization of both ganglionic and neuromuscular nicotinic receptors. Thus, like nicotine, chronic treatment with epibatidine might be expected to lead to tolerance. These studies establish epibatidine as a tool for the study of nicotinic pathways involved in pain perception. © 1995 Wiley-Liss, Inc.     

The unusual nature of epibatidine responses at the α4β2 nicotinic acetylcholine receptor

The identification of an equatorial frog toxin, epibatidine, as a potent non-morphinic analgesic, selective for neuronal nicotinic acetylcholine receptors, provoked a marked renewal in our understanding of pain and its mechanisms. In this work we have examined the effects of epibatidine at the major brain rat α4β2 nicotinic acetylcholine receptor expressed in a cell line. Fast drug applications obtained with a modified liquid filament system were used for the analyses of the currents evoked by acetylcholine, nicotine and epibatidine. Characterized by a slow onset and offset, epibatidine responses were of smaller amplitude to those evoked by acetylcholine or nicotine. About a thousand times more sensitive to epibatidine than acetylcholine, the α4β2 receptor also displayed a more pronounced apparent desensitization to this compound. Finally, overnight exposure to 1 nM epibatidine failed to produce the functional upregulation observed with nicotine. These data indicate that, at the rat α4β2 receptor, epibatidine acts as a partial agonist causing a pronounced inhibition of agonist evoked currents at concentrations that do not activate the receptors.     

Neuronal nicotinic receptors: a perspective on two decades of drug discovery research

Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.     

Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists

Activation of spinal nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent nicotinic agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three nicotinic agonists—epibatidine, cytisine and nicotine—were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine>cytisine>nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other nicotinic agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antagonist, -lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro-β-erythroidine, also a competitive antagonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N-methyl- -aspartate receptor antagonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 μg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 μg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal nicotinic agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal nicotinic receptors as suggested by the antagonist studies.     

Enhanced antinociception by nicotinic receptor agonist epibatidine and adrenal medullary transplants in the spinal subarachnoid space

Adrenal medullary transplants in the spinal subarachnoid space can reduce nociception, via the release of catecholamines and other analgesic substances, and this may be enhanced by stimulation of transplanted chromaffin cell surface nicotinic acetylcholine receptors (nAChRs). In addition, spinal nAChRs have been implicated in modulating nociception and can interact synergistically with alpha-adrenergic agents. Thus, enhanced antinociception by potent nAChR agonists such as frog skin derivative epibatidine in adrenal-transplanted animals could potentially occur via multiple mechanisms, including nicotinic-alpha-adrenergic synergy and stimulation of chromaffin cell nicotinic receptors. In order to test this, male Sprague-Dawley rats were implanted with intrathecal catheters and either adrenal medullary or control striated muscle transplants in the spinal subarachnoid space at the lumbar enlargement. Animals were tested for nociceptive responses before and after intrathecal injection of several doses of epibatidine using acute analgesiometric tests (tail flick, paw pressure) and the formalin test. After adrenal medullary, but not control, transplantation, nociceptive thresholds to acute noxious stimuli were slightly but consistently elevated, and phase 2 formalin responses decreased. Following intrathecal injection of epibatidine, acute nociceptive response latencies were modestly elevated and phase 2 formalin flinches modestly suppressed in control animals, but only at the highest dose test, with some attendant motor side-effects. In contrast, in adrenal medullary-transplanted animals, epibatidine elevated responses to acute noxious stimuli and markedly suppressed phase 2 formalin responses in a dose-related fashion. The enhanced antinociceptive effect following epibatidine was attenuated with either nAChR antagonist mecamylamine or alpha-adrenergic receptor antagonist phentolamine. The current results demonstrate that intrathecal injection of the nAChR ligand epibatidine can produce significant antinociception in adrenal-transplanted rats in both acute and tonic nociceptive tests and suggest that the use of nicotinic agents in combination with adrenal medullary transplantation could provide maximal therapeutic benefit by synergistically improving antinociception while avoiding the detrimental side-effects of these agents.     

Recent developments in the synthesis of nicotinic acetylcholine receptor ligands

The extraordinary pharmacology of nicotine and epibatidine have indicated the potential for nicotinic acetylcholine receptor (nAChR) ligands to serve as a new therapeutic class for a host of CNS disorders. Many such ligands are natural products, or analogs thereof, which represent a significant challenge to the synthetic chemist. Synthesis of such molecules often serves as a showcase to demonstrate the potential of newly developed methodology. This synthetic challenge coupled with the promise of pharmacological activity in compounds possessing the nicotinic pharmacophore has stimulated a great deal of synthetic activity over the last five years. The present report provides an overview of novel synthetic methodology occurring during this period directed toward the synthesis of compounds with presumed affinity for the neuronal nAChR. Syntheses chosen for review here represent the major efforts toward molecules such as epibatidine analogs, anatoxin-a, nicotine and related alkaloids, conformationally constrained nicotine derivatives, cytisine and methyllycaconitine (MLA).     

Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor

The rat alpha9 nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus laevis oocytes and tested for its sensitivity to a wide variety of cholinergic compounds. Acetylcholine (ACh), carbachol, choline and methylcarbachol elicited agonist-evoked currents, giving maximal or near maximal responses. Both the nicotinic agonist suberyldicholine as well as the muscarinic agonists McN-A-343 and methylfurtrethonium behaved as weak partial agonists of the receptor. Most classical cholinergic compounds tested, being either nicotinic (nicotine, epibatidine, cytisine, methyllycaconitine, mecamylamine, dihydro-beta-erythroidine), or muscarinic (muscarine, atropine, gallamine, pilocarpine, bethanechol) agonists and antagonists, blocked the recombinant alpha9 receptor. Block by nicotine, epibatidine, cytisine, methyllycaconitine and atropine was overcome at high ACh concentrations, suggesting a competitive type of block. The present results indicate that alpha9 displays mixed nicotinic-muscarinic features that resemble the ones described for the cholinergic receptor of cochlear outer hair cells (OHCs). We suggest that alpha9 contains the structural determinants responsible for the pharmacological properties of the native receptor.     

Analgesic and toxic effects of neonicotinoid insecticides in mice.

Several nicotinic agonists with the 6-chloro-3-pyridinyl moiety are potent insecticides (e.g., the neonicotinoids imidacloprid and thiacloprid) while others are candidate nonopioid and nonantiinflammatory analgesics (i.e., epibatidine and several heterocyclic analogs). This study examines the hypothesis for the first time that the neonicotinoid insecticides and their imine metabolites and analogs display analgesic (antinociceptive) activity or adverse toxic effects associated with their action on binding to the alpha 4 beta 2 nicotinic acetylcholine receptor (AChR) subtype. Seven 6-chloro-3-pyridinyl compounds were studied, i.e., imidacloprid and thiacloprid, the corresponding imines and an olefin derivative, a nitromethylene analog, and (+/-)-epibatidine. Like (-)-nicotine and carbachol, they all act as full agonists in the (86)rubidium ion efflux experiment with intact mouse fibroblast M10 cells stably expressing the alpha 4 beta 2 nicotinic AChR. Their agonist action is correlated with binding affinity to the alpha 4 beta 2 receptor from M10 cells. Imidacloprid, thiacloprid, and their imine analogs are not antinociceptive agents in mice by abdominal constriction and hot plate analgesic tests. Their agonist actions at the alpha 4 beta 2 receptor correlate instead with their toxicity. Surprisingly, the nitromethylene analog, a weak agonist, is as potent as (-)-nicotine in inducing antinociception, and the effect persists longer than that caused by (-)-nicotine. However, mecamylamine (1 mg/kg) prevents antinociception induced by (-)-nicotine but not by the nitromethylene analog. Interestingly, this nitromethylene neonicotinoid insecticide gives 80-100% mortality within 15 min at 3 mg/kg with mecamylamine pretreatment at 2 mg/kg, doses at which each agent alone gives no lethality. Therefore, analgesic and toxic effects of the nitromethylene analog differ in their mechanism of action from (-)-nicotine and (+/-)-epibatidine.     

Synthesis,nicotinic acetylcholine receptor binding,and antinociceptive properties of 2-exo-2-(2',3'-disubstituted 5'-pyridinyl)-7-azabicyclo[2.2.1]heptanes: epibatidine analogues

A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in vitro for potency at nicotinic acetylcholine receptors (nAChRs) and in vivo for antinociception activity in the tail-flick and hot-plate models of acute pain and for their ability to affect core body temperature. Compounds that possessed electron-withdrawing groups (F, Cl, Br, and I) in both the 2'- and the 3'-positions showed affinities at the nAChR similar to epibatidine. However, in vivo efficacy did not correlate with affinity. 2-exo-(3'-Amino-2'-chloro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing amino group in the 3'-position, produced the highest affinity. Compound 2i was also the most selective epibatidine analogue with a K(i) of 0.001 nM at alphabeta nAChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K(i) ratio of 14,000, twice that of epibatidine. In vivo testing revealed that this compound potently inhibited nicotine-induced antinociception with AD(50) values below 1 microg/kg. Surprisingly, this same compound was also an agonist at higher doses (ED(50) approximately 20 microg/kg). Thus, the addition of the 3'-amino group to epibatidine confers potent antagonist activity to the compound with little effect on agonist activity. 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combined with a 3'-bromo or 3'-iodo group showed in vitro and in vivo nAChR properties similar to nicotine.     

Neuronal nicotinic receptors as analgesic targets: It's a winding road

Along with their well known role in nicotine addiction and autonomic physiology, neuronal nicotinic receptors (nAChRs) also have profound analgesic effects in animal models and humans. This is not a new idea, even in the early 1500s, soon after tobacco was introduced to the new world, its proponents listed pain relief among the beneficial properties of smoking. In recent years, analgesics that target specific nAChR subtypes have shown highly efficacious antinociceptive properties in acute and chronic pain models. To date, the side effects of these drugs have precluded their advancement to the clinic. This review summarizes the recent efforts to identify novel analgesics that target nAChRs, and outlines some of the key neural substrates that contribute to these physiological effects. There remain many unanswered mechanistic questions in this field, and there are still compelling reasons to explore neuronal nAChRs as targets for the relief of pain.     

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 2-exo-2-(2'-substituted-3'-phenyl-5'-pyridinyl)-7-azabicyclo[2.2.1]heptanes. Novel nicotinic antagonist.

A series of 2'-substituted-3'-phenyl epibatidine analogues were synthesized and evaluated for inhibition of binding at nicotine acetylcholine receptors and for antinociceptive properties in mice. The introduction of a bulky phenyl group at the 3'-position exerted a profound influence on both receptor binding and antinociceptive effects. Substitution of different groups at the 2'-position distinguished between agonist and antagonist properties. These results demonstrate that structural requirements for receptor activities and recognition are distinctively different.     

Recent advances in the development of 14-alkoxy substituted morphinans as potent and safer opioid analgesics

Morphine and other opioid morphinans produce analgesia primarily through μ opioid receptors (MORs), which mediate beneficial but also non-beneficial actions. There is a continued search for efficacious opioid analgesics with reduced complications. The cornerstone in the development of 14-alkoxymorphinans as novel analgesic drugs was the synthesis of the highly potent MOR agonist 14-O-methyloxymorphone. This opioid showed high antinociceptive potency but also the adverse effects associated with morphine type compounds. Further developments represent the introduction of a methyl and benzyl group at position 5 of 14-O-methyloxymorphone leading to the strong opioid analgesics 14-methoxymetopon and its 5-benzyl analogue, which exhibited less pronounced side effects than morphine although interacting selectively with MORs. Introduction of arylalkyl substituents such as phenylpropoxy in position 14 led to a series of extremely potent antinociceptive agents with enhanced affinities at all three opioid receptor types. During the past years, medicinal chemistry and opioid research focused increasingly on exploring the therapeutic potential of peripheral opioid receptors by peripheralization of opioids in order to minimize the occurrence of centrally-mediated side effects. Strategies to reduce penetration to the central nervous system (CNS) include chemical modifications that increase hydrophilicity. Zwitterionic 6-amino acid conjugates of 14-Oalkyloxymorphones were developed in an effort to obtain opioid agonists that have limited access to the CNS. These compounds show high antinociceptive potency by interacting with peripheral MORs. Opioid drugs with peripheral site of action represent an important target for the treatment of severe and chronic pain without the adverse actions of centrally acting opioids.     

Influence of nicotinic receptor modulators on CB2 cannabinoid receptor agonist (JWH133)-induced antinociception in mice

Delta9-tetrahydrocannabinol is the active component in cannabis and has long been associated with pain relief. This effect is believed to be mediated through central and peripheral CB1 and peripheral CB2 receptors. We have explored the possible antinociceptive effect of a CB2 receptor agonist, JWH133, using the formalin test in mice. The drug was administered by the intracerebroventricular and intraperitoneal routes. Although no antinociceptive effect was observed after intracerebroventricular administration of JWH133, when the drug was administered by the intraperitoneal route, it produced an analgesic effect. The influence of nicotinic cholinergic receptor modulators, nicotine and mecamylamine, on antinociceptive effect of JWH133 was also studied. Nicotine increased and mecamylamine decreased the antinociceptive effect of JWH133. It is concluded that JWH133-induced analgesia is influenced by nicotinic cholinergic receptor activity.