Dorsal root ganglion (DRG) expression levels of Chrna6, the gene that encodes the nicotinic acetylcholine receptor α6 subunit, are highly correlated with mechanical allodynia in mice, and variability in the gene is also associated with chronic pain in humans,
Furthermore, the analgesic effect of nicotine did not depend on the nicotinic receptor’s α4 subunit, suggesting a possible explanation for a lack of progress in analgesic drug discovery efforts focused on that particular subunit.
“These findings really advance our understanding of the role of nicotinic receptors in pain and provide an entry point for new drug discovery efforts focused on selective activation of the α6 subunit,”
With 41 authors located at 18 different research institutions, the new study highlights the utility of a global translational research effort, Arneric added.
Nicotinic acetylcholine receptors (nAChRs), which are hetero- or homopentameric ligand-gated ion channels consisting of α and β subunits, have garnered interest as potential analgesic drug targets for many years. Work to date has largely focused on the subunit with the highest central nervous system expression, α4, with little success due to a narrow therapeutic window and significant side effects
The Chrna6 connection
Experiments with Chrna6 mutant mice also indicated a role for the gene in neuropathic pain.
The researchers next examined the role of the α6 receptor in the known anti-allodynic effects of nicotine administration in inflammatory and neuropathic pain models
nicotine did not produce an anti-allodynic effect in Chrna6 knockouts.
Both peripheral and spinal nicotine-induced anti-allodynia were abolished in Chrna6 knockouts but were preserved in Chrna4 knockouts, while anti-allodynia was reduced in Chrna6 knockouts and completely absent in Chrna4 knockouts following supraspinal nicotine.
“The conclusion that we came to was that α4 plays an important role in supraspinal nicotinic analgesia … but outside the brain, it’s all about α6,”
the mechanism underlying α6’s analgesic effect involved a physical and functional interaction with P2X2/3 receptors, which have been linked to pain in previous studies.
The study also examined the association between CHRNA6 single nucleotide polymorphisms (SNPs) and chronic pain in humans
“On the one hand, the human data were completely supportive that this gene can play a role in pain…
On the other hand, the number of people with the variant was so small that there’s no way the gene plays any role in chronic pain susceptibility for the vast majority of individuals—it’s simply too rare, he continued.
“As with many mediators involved in pain, manipulation of [the α6] system in isolation is unlikely to provide the analgesic panacea that patients need, but the findings provide another important target to investigate in preclinical and clinical settings,”
“We put this into the world in hopes it will spur rejuvenation of nicotinic drug development for pain by those who do that,”