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 α4β2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of α4β2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for α4β2 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 α4β2 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 nicotine-evoked 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 dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the α4β2 nAChRs by using competitive α4β2 antagonist dihydro-β-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to α4β2 nAChRs.

CONCLUSIONS:

The present results suggest that allosteric modulation of α4β2 nAChR may provide new strategies in chronic neuropathic pain.

SIGNIFICANCE:

α4β2 nAChRs are involved in pain modulation. dFBr, a PAM at α4β2 nAChRs, 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.

• Authors: D Bagdas, D Ergun, A Jackson, W Toma, M K Schulte, M I Damaj
• Journal: European journal of pain (London, England) (Eur J Pain) Vol. 22 Issue 1 Pg. 84-93 (01 2018) ISSN: 1532-2149 [Electronic] England
• PMID: 28809075 (Publication Type: Journal Article)
• Copyright: © 2017 European Pain Federation - EFIC®.

Chemical References

• Hydrocarbons, Brominated
• Indole Alkaloids
• Nicotinic Agonists
• Receptors, Nicotinic
• desformylflustrabromine
• nicotinic receptor alpha4beta2
• Nicotine

Topics

• Allosteric Regulation (drug effects)
• Animals
• Disease Models, Animal
• Hydrocarbons, Brominated (pharmacology, therapeutic use)
• Indole Alkaloids (pharmacology, therapeutic use)
• Male
• Mice
• Neuralgia (drug therapy, metabolism)
• Nicotine
• Nicotinic Agonists (pharmacology, therapeutic use)
• Receptors, Nicotinic (metabolism)