Physiological Basis of Hereditary Pain Syndrome Identified

Yale researchers report the first explanation of the physiological basis for the inherited, chronic pain syndrome erythromelalgia in an article today in the Journal of Neuroscience.

Erythromelalgia has largely remained an obscure disease with unknown cause until the advent of the genomics era. The article describes the physiological abnormality which leads to erythromelalgia, a condition characterized by intermittent intense burning pain in the extremities and symptoms of redness, heat, pain and swelling.

Using the catalog of human genes, recent studies linked erythromelalgia to two mutations in SCN9A, a gene that codes for a voltage-gated sodium channel of the subtype Nav1.7. Voltage-gated sodium channels are present along the length of nerve fibers where they serve as molecular batteries in generating and transmitting nerve signals.

A research team led by Stephen Waxman, M.D., chair and professor of neurology and director of the Veterans Affairs Rehabilitation Research Center in West Haven, showed how abnormal function of Nav1.7 channels, as a result of these mutations, leads to inappropriate, spontaneous firing of pain-signaling nerve cells.

Waxman and colleagues, Sulayman Dib-Hajj and Theodore Cummins, previously discovered the role of Nav1.7 in generating impulses within pain-signalling nerve cells. This study set out to examine the contribution of mutations in Nav1.7 to the pathophysiology of erythromelalgia. They recorded electrical currents from cells with mutant Nav1.7 and compared them with cells expressing normal Nav1.7.

The investigators observed that mutant Nav1.7 channels displayed altered behavior, which can cause neurons to turn on more easily and poise them to fire signals at higher than normal rates. Such a behavior is consistent with numerous findings linking hyper-excitability of pain-signaling nerve cells to pain syndromes.

“We are excited about these findings because they may teach us about the molecular basis for pain associated with inflammation and nerve injury,” Waxman said. “Hopefully the findings will contribute to the development of new therapies for erythromelalgia.”

Citation: Journal of Neuroscience, Vol. 24: pp 8232-8236, September 24, 2004