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

Eur J Pain. 2018 Jan;22(1):84-93. doi: 10.1002/ejp.1092. Epub 2017 Aug 14.


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.

MeSH terms

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


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