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Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain
Author(s) -
Bagdas D.,
Ergun D.,
Jackson A.,
Toma W.,
Schulte M.K.,
Damaj M.I.
Publication year - 2018
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1092
Subject(s) - nicotine , nicotinic agonist , neuropathic pain , allosteric modulator , pharmacology , acetylcholine receptor , allosteric regulation , agonist , partial agonist , chemistry , medicine , neuroscience , receptor , psychology
Abstract Background Neuronal nicotinic acetylcholine receptors ( nAChR s) are ligand‐gated ion channels. The α4β2 subtype of nAChR s plays an important role in the mediation of pain and several nicotine‐evoked responses. Agonists and partial agonists of α4β2 nAChR s show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non‐selective nAChR agonist with a high affinity for α4β2 nAChR s, is well‐known. There is a growing body of evidence pointing to allosteric modulation of nAChR s as an alternative treatment strategy in experimental pain. Desformylflustrabromine ( dFB r) is a positive allosteric modulator ( PAM ) at α4β2 nAChR s that enhances agonist responses without activating receptors. We hypothesized that dFB r may enhance nicotine‐induced antinociception. Methods The present study investigated whether dFB r could attenuate mouse chronic constriction injury ( CCI )‐induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine‐evoked antiallodynic response. Results We found that subcutaneous administration of dFB r failed to reduce pain behaviour on its own. However, the combination of dFB r with nicotine significantly reversed neuropathic pain behaviour dose‐ and time‐dependently without motor impairment. Our data revealed that this effect was mediated by the α4β2 nAChR s by using competitive α4β2 antagonist dihydro‐β‐erythroidine. In addition, dFB r failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFB r is unique to α4β2 nAChR s. Conclusions The present results suggest that allosteric modulation of α4β2 nAChR may provide new strategies in chronic neuropathic pain. Significance α4β2 nAChR s are involved in pain modulation. dFB r, a PAM at α4β2 nAChR s, potentiates the nicotine response dose‐dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of α4β2* nAChR may provide new strategies in chronic neuropathic pain.