Allosteric modulation of α4β2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain

Abstract

Background: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The a4b2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of a4b2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for a4b2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at a4b2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. Methods: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotineevoked antiallodynic response. Results: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour doseand time-dependently without motor impairment. Our data revealed that this effect was mediated by the a4b2 nAChRs by using competitive a4b2 antagonist dihydro-b-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to a4b2 nAChRs. Conclusions: The present results suggest that allosteric modulation of a4b2 nAChR may provide new strategies in chronic neuropathic pain. Significance: a4b2 nAChRs are involved in pain modulation. dFBr, a PAM at a4b2 nAChRs, potentiates the nicotine response dosedependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of a4b2* nAChR may provide new strategies in chronic neuropathic pain.

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

“…Our results also demonstrated that the co-administration of inactive doses of dFBr and TC-2403 can lead to procognitive effects. This finding corroborates previous reports in which dFBr enhanced nicotine-induced antinociception in a mouse model of neuropathic pain [39]. Similarly, NS9283 augmented the antinociceptive properties of the α4β2-agonist ABT-594 in various pain models [40,41].…”

Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN

“…For acute administration, nicotine was injected i.p. at doses of 0.3, 0.6, or 0.9 mg/kg (Di Cesare Mannelli et al, 2013;Bagdas et al, 2017). Nicotine at doses of 6, 12, or 24 mg/kg per day was also administered chronically via 7-day s.c. osmotic minipumps (model 1007D; Alzet, Cupertino, CA), which were implanted 2 days prior to paclitaxel treatment (Alsharari et al, 2015).…”

Effect of nicotine and alpha‐7 nicotinic modulators on visceral pain‐induced conditioned place aversion in mice

“…injection of AA, to compare the potency of nicotine in blocking nociceptive reflex behaviour and place aversion. We have previously demonstrated that nicotine can be antinociceptive in several mouse models of pain (Damaj et al., ; Bagdas et al., , ; Kyte et al., ). In our current study, nicotine was found to be more potent (27‐fold) in alleviating the aversive state than the stretching responses induced by AA injection.…”