23 September 2020
Dealing with chronic pain
Published online 26 May 2015
A gene identified in mice and humans could offer a target for new analgesic drugs.
An international research team has identified a gene that determines sensitivity to chronic pain, opening up new avenues for the development of novel analgesics1.
Jeffrey Mogil of McGill University in Montréal and his colleagues looked at 25 different mouse strains to examine genome-wide expression levels in the dorsal root ganglia (DRG) and identify genes associated with hypersensitivity to mechanical pressure, one of the main symptoms of chronic pain.
They identified the Chrna6 gene, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAchR), and is expressed in a subset of pain-sensing DRG cells.
Mice lacking this gene are hypersensitive to mechanical pressure, whereas those over-expressing the gene were less sensitive to it. The analgesic effects of nicotine, which activates nAchRs, is also abolished in mice lacking the gene.
Further experiments showed that the increased mechanical sensitivity which follows nerve injury is accompanied by reduced Chrna6 expression, and that nicotinic receptors containing the α6 subunit normally determines this sensitivity by inhibiting P2X2 and P2X3 pain receptors, which are also expressed by DRG cells.
Finally, the researchers genotyped 249 patients suffering from chronic pain, and found that the few carrying two copies of CHRNA6 reported substantially higher pain levels than those carrying just one.
“This suggests that the ideal target for a nicotinic analgesic would be a drug targeting α6 that didn't cross the blood-brain barrier,” says Mogil, “so hopefully others will follow up these findings.”
Wieskopf, J. S. et al. The nicotinic a6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci. Transl. Med. doi: http://dx.doi.org/10.1126/scitranslmed.3009986 (2015).