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Neuronal nicotinic acetylcholine receptors (nAChRs) of the cholinergic system have been linked to antinociception, and therefore could be an alternative target for pain alleviation. nAChR activity has been shown to be regulated by the nicotinic modulator, lynx1, which forms stable complexes with nAChRs and has a negative allosteric action on their function. The objective in this study was to investigate the contribution of lynx1 to nicotine-mediated antinociception.  Lynx1  contribution was investigated by mRNA expression analysis and electrophysiological responses to nicotine in the dorsal raphe nucleus (DRN), a part of the pain signaling pathway.  In vivo  antinociception was investigated in a test of nociception, the hot-plate analgesia assay with behavioral pharmacology.  Lynx1 /α4β2 nAChR interactions were investigated using molecular dynamics computational modeling. Nicotine evoked responses in serotonergic and GABAergic neurons in the DRN are augmented in slices lacking  lynx1  ( lynx1 KO). The antinociceptive effect of nicotine and epibatidine is enhanced in  lynx1 KO mice and blocked by mecamylamine and DHβE. Computer simulations predict preferential binding affinity of  lynx1  to the α:α interface that exists in the stoichiometry of the low sensitivity (α4) 3 (β2) 2  nAChRs. Taken together, these data point to a role of  lynx1  in mediating pain signaling in the DRN through preferential affinity to the low sensitivity α4β2 nAChRs. This study suggests that  lynx1  is a possible alternative avenue for nociceptive modulation outside of opioid-based strategies.

Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation