Reviewα4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain
Graphical abstract
Distribution of α4β2* neuronal nicotinic acetylcholine receptor in various centers of pain pathway.
Introduction
Pain affects the mental and physical well being that significantly interfere with the quality of our daily life. Hence, studying nociceptive mechanisms and identifying potential targets for the treatment of pain have become the top priorities in health organizations as well as pharmaceutical companies (Luo, 2004). While opioids and NSAIDS (Non steroidal anti-inflammatory drugs) remain the most commonly prescribed pain medications, these drugs cause side effects which include drowsiness, nausea, respiratory depression, vomiting, constipation, dependence and gastrointestinal disturbances (Woodcock, 2009). Despite strong analgesic activity, some neuropathic pain conditions are resistant to opioid therapy (Ollat and Cesaro, 1995, Mc Cormick and Schreiner, 2001, Smith, 2012). Antidepressant, anticonvulsant and local anaesthetic drugs are being currently used for the treatment of neuropathic pain, but they offer limited therapeutic efficacy (Finnerup et al., 2010).
The analgesic effects of nicotine have been demonstrated in preclinical and clinical studies. It was shown that nicotine given as nasal spray or transdermal patch has analgesic effects in clinical studies, however patients reported higher levels of nausea and increase in heart rate (Flood and Daniel, 2004, Hong et al., 2008, Yagoubian et al., 2011). The anti-nociceptive effects of nicotine are thought to be mediated through nicotinic acetylcholine receptor and attenuated by the treatment of mecamylamine (brain penetrant nicotinic acetylcholine receptor antagonist) in preclinical studies (Cooley et al., 1990, Iwamoto, 1991, Tripathi et al., 1982). The most widely distributed nicotinic receptor subtype in the brain is α4β2* heteromeric (α-bungarotoxin-insensitive) nicotinic acetylcholine receptor (Hogg et al., 2003, McGehee and Role, 1995). Nicotine acts as an agonist and display higher selectivity towards these receptor (Hogg and Bertrand, 2007). First evidence implicating α4β2* neuronal nicotinic acetylcholine receptor in the pain modulation comes from studies demonstrating that α4- and β2-knockout mice showed reduced anti-nociceptive effect of nicotine (Marubio et al., 1999). The anatomical distribution of α4β2* neuronal nicotinic acetylcholine receptor in the brain and the spinal cord supports a role of these receptor in nociceptive transmission (Gotti et al., 2006, Shi et al., 2010). Activation of presynaptic α4β2* neuronal nicotinic acetylcholine receptor increases the release of multiple neurotransmitters in the brain including acetylcholine, dopamine, γ-amino butyric acid (GABA) and norepinephrine (Jensen et al., 2005, Sher et al., 2004).
Section snippets
Site and mechanism of action of α4β2* neuronal nicotinic acetylcholine receptor ligands in reducing neuropathic pain and inflammatory pain
Several sites of action have been proposed for the anti-nociceptive action of α4β2* neuronal nicotinic acetylcholine receptor ligands including spinal and supraspinal sites. α4β2* neuronal nicotinic acetylcholine receptor are present in nucleus raphe magnus (NRM), dorsal raphe (DR), locus coeruleus (LC) (Bitner et al., 1998, Cucchiaro and Commons, 2003, Cucchiaro et al., 2005, Galindo-Charles et al., 2008, Gotti et al., 2006). Many of these areas are thought to play a major role in descending
Agonist, partial agonist and allosteric modulators of α4β2* neuronal nicotinic acetylcholine receptor in pain modulation
The genesis for pain management through α4β2* neuronal nicotinic acetylcholine receptor initiated after the isolation of epibatidine from the skin of frog Epipedobutes tricolor which is approximately 200-fold more potent than morphine in producing analgesia (Sullivan and Bannon, 1996). Epibatidine is agonist at α4β2* neuronal nicotinic acetylcholine receptor and interacts with several of the other subtypes including α7 and α4β2* neuronal nicotinic acetylcholine receptor (Sullivan et al., 1994).
Is agonism at α4β2* neuronal nicotinic acetylcholine receptor sufficient to produce broad spectrum analgesia?
Nicotine is prototype agonist that shows a broad spectrum anti-nociceptive and anti-inflammatory action. α7 nicotinic agonists have shown analgesic like activity in some of pain models like tail flick (Damaj et al., 2000) and post operative pain models (Rowley et al., 2008). Involvement of α5 containing neuronal nicotinic acetylcholine receptor in pain modulation was shown by studies using knock down of α5 subunit in the rat with spinal nerve ligation (Vincler and Eisenach, 2005). This was
Clinical development of α4β2* neuronal nicotinic acetylcholine receptor agonists
α4β2* neuronal nicotinic acetylcholine receptor agonists are a recent development in the study of potential treatment of pain, and they show a broad spectrum anti-nociceptive activity in preclinical models of both inflammatory and neuropathic pain. Proof of concept for α4β2* neuronal nicotinic acetylcholine receptor agonists as a new class of compounds for the treatment of neuropathic pain was demonstrated with ABT-594. However, high incidence of adverse effects like nausea, dizziness and
Conclusion
α4β2* neuronal nicotinic acetylcholine receptor regulates different process of pain pathways by inhibiting the incoming pain signals and modulate the pain perception. α4β2* neuronal nicotinic acetylcholine receptor ligands have been shown to be effective in a number of animal models of neuropathic and inflammatory pain. The clinical trials of α4β2* neuronal nicotinic acetylcholine receptor agonists showed mixed results and raise the possibility of additional neural nicotinic receptor involved
Declaration of interest
All authors are current employees of Suven Life Sciences Ltd.
Acknowledgment
The authors wish to acknowledge the support received from Mr. Venkateswarlu Jasti, CEO, Suven Life Sciences Ltd., Hyderabad, India.
References (112)
- et al.
Analgesic action of nicotine on tibial nerve transection (TNT)-induced mechanical allodynia through enhancement of the glycinergic inhibitory system in spinal cord
Life Sci.
(2006) - et al.
Neuronal nicotinic receptors: a perspective on two decades of drug discovery research
Biochem. Pharmacol.
(2007) - et al.
ABT-594, a novel cholinergic channel modulator, is efficacious in nerve ligation and diabetic neuropathy models of neuropathic pain
Brain Res.
(1998) - et al.
Allosteric modulation of nicotinic acetylcholine receptors
Biochem. Pharmacol.
(2007) - et al.
Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat
Brain Res.
(2000) - et al.
Analgesic and toxic effects of ABT-594 resemble epibatidine and nicotine in rats
Pain
(2000) - et al.
Effect of pCPA on nicotine-induced analgesia
Pharmacol. Biochem. Behav.
(1990) - et al.
The locus coeruleus nucleus as a site of action of the anti-nociceptive and behavioral effects of the nicotinic receptor agonist, epibatidine
Neuropharmacology
(2006) - et al.
Tolerance to the antinociceptive effect of epibatidine after acute and chronic administration in mice
Eur. J. Pharmacol.
(1996) - et al.
The anti-nociceptive effects of alpha7 nicotinic agonists in an acute pain model
Neuropharmacology
(2000)
Anti-nociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist ABT-594 in mice
Eur. J. Pharmacol.
The role of neuronal nicotinic acetyicholine receptors in antinociception: effects of ABT-594
J. Physiol.
Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics
Rev. Biochem. Pharmacol.
The evidence for pharmacological treatment of neuropathic pain
Pain
Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain
Pain
Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn
Brain Res.
Brain nicotinic acetylcholine receptors: native subtypes and their relevance
Trends Pharmacol. Sci.
Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors
Biochem. Pharmacol.
Nicotinic acetylcholine receptors: from basic science to therapeutics
Pharmacol. Ther.
A-366833: A novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane a4b2 nicotinic acetylcholine receptor selective agonist: synthesis, analgesic efficacy and tolerability profile in animal models
Biochem. Pharmacol.
Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert centrally mediated antinociception in the rat cyclophosphamide cystitis model of visceral pain
J. Pain
Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)- epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain
Pain
Nicotinic cholinergic receptors: potential targets for inflammatory pain relief
Pain
α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain
Biochem. Pharmacol.
Nicotine-induced up-regulation and desensitization of α4β2 neuronal nicotinic receptors depend on subunit ratio
J. Biol. Chem.
ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model
Eur. J. Pharmacol.
Presynaptic nicotinic acetylcholine receptors enhance GABAergic synaptic transmission in rat periaqueductal gray neurons
Eur. J. Pharmacol.
Anti-nociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain
Eur. J. Pharmacol.
Pharmacological characterization of SIB-1663, a conformationally rigid analog of nicotine
Brain Res.
Neuropathy-specific analgesic action of intrathecal nicotinic agonists and its spinal GABA-mediated mechanism
Brain Res.
A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain
Pain
Efficacy and safety of the α4β2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain
Pain
Spinal mechanisms underlying A-85380-induced effects on acute thermal pain
Brain Res.
Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain
Pain
Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones
Brain Res.
Modulation of inhibitory synaptic activity by a non-alpha4beta2, non-alpha7 subtype of nicotinic receptors in the substantia gelatinosa of adult rat spinal cord
Pain
Efficacy and safety of the novel α4β2 neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study
Psychopharmacology (Berlin)
(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: I. In vitro characterization
J. Pharmacol. Exp. Ther.
A randomized, double-blind, placebo-controlled Phase 2 study of the a4b2 agonist ABT-894 in adults with ADHD
Neuropsychopharmacology
Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors
Science
Alpha7-nicotinic receptors modulate nicotine-induced reinforcement and extracellular dopamine outflow in the mesolimbic system in mice
Psychopharmacology (Berlin)
Role of the nucleus raphe magnus in antinociception produced by ABT-594: Immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotonergic neurons
J. Neurosci.
Characterization of the electrophysiological, biochemical and behavioral effects of epibatidine
J. Pharmacol. Exp. Ther.
Chronic exposure to nicotine upregulates the human α4β2 nicotinic acetylcholine receptor function
J. Neurosci.
Different methods of assessing nicotine-induced antinociception may engage different neural mechanisms
Psychopharmacology
Associative tolerance to nicotine analgesia in the rat: tail-flick and hot-plate tests
Exp. Clin. Psychopharmacol.
Dose-response analyses of associative tolerance to nicotine analgesia in the rat: tail-flick and hot-plate tests
Exp. Clin. Psychopharmacol.
Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats
Neuropsychopharmacology
Enhanced inhibitory synaptic transmission in the spinal dorsal horn mediates anti-nociceptive effects of TC-2559
Mol. Pain
Alpha 4 nicotinic acetylcholine receptor subunit links cholinergic to brainstem monoaminergic neurotransmission
Synapse
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