Review
α4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain

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Abstract

α4β2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. α4β2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, γ-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which α4β2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective α4β2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of α4β2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by α4β2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various α4β2* neuronal nicotinic acetylcholine receptor ligands.

Graphical abstract

Distribution of α4β2* neuronal nicotinic acetylcholine receptor in various centers of pain pathway.

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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.

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