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

alpha 4 beta 2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. alpha 4 beta 2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, gamma-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which alpha 4 beta 2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective alpha 4 beta 2* 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 alpha 4 beta 2* 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 alpha 4 beta 2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various alpha 4 beta 2* neuronal nicotinic acetylcholine receptor ligands. (C) 2013 Elsevier B.V. All rights reserved.