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Molecular basis for pain and inflammation in Erythromelalgia

Yale University : 17 March, 2007  (Technical Article)
A single mutation in an ion channel gene can produce opposing effects on signaling within the nervous system depending on the nerve cells in which it operates, shedding light on the molecular basis for erythromelalgia, a debilitating neuropathic pain syndrome, Yale School of Medicine researchers report this week in the Proceedings of the National Academy of Sciences.
This paper provides novel insights into how a single mutation can produce multiple symptoms. The study demonstrates that a mutation in the sodium channel Nav 1.7 causes over-excitability in one type of neuron and under-excitability in another type of neuron, according to Stephen Waxman, M.D., chair of the Department of Neurology and director of the West Haven Veteran Administration Rehabilitation Research Center.

Erythromelalgia is characterized by attacks of burning pain that are often triggered by a slight elevation in skin temperature. The pain is so severe and debilitating that patients often seek relief by immersing the affected areas in ice water, and avoiding activities that even mildly elevate body temperature. The attacks of pain are usually accompanied by warmth and redness of the hands and feet and can occur several times per day and last for minutes to several days. There is currently no effective treatment for erythromelalgia.

Sodium channels act like molecular batteries that allow neurons to produce and transmit nerve impulses. Recent studies have shown that mutations in the sodium channel Nav 1.7 cause inherited erythromelalgia. The mutation predisposes pain-signaling neurons to be over-excitable and fire rapid bursts of impulses in response to normally non-painful stimuli. The brain interprets these impulses as signaling a painful stimulus.

The Yale research team, which included Anthony Rush, Sulayman Dib-Hajj, Shujun Lui and Joel Black, together with Theodore Cummins from Indiana University School of Medicine, measured the electrophysiology of the mutant in both sensory and sympathetic neurons, the two types of neurons in which Nav 1.7 channel normally functions. They found that, in sensory neurons the mutation produced over-excitability. In contrast, the mutant channel produced under-excitability in sympathetic neurons, nearly silencing them. Sympathetic neurons innervate blood vessels and control their caliber, so these findings provide an explanation for the abnormal blood flow that is seen in the limbs of people with erythromelalgia.

The Yale team further examined the molecular basis for the apparently paradoxical effects of this mutation. Manipulating molecules within sympathetic neurons, they showed that sensory neurons and sympathetic neurons contain different sets of ion channels, accounting for the difference in their firing response.

Identification of the precise role of mutant Nav 1.7 in pain sensing neurons as well as in neurons that control blood flow should enable the development of therapies to effectively alleviate pain and inflammation in people with erythromelalgia and related neuropathic pain syndromes.

These results may also be relevant to non-inherited pain syndromes as work at Yale and elsewhere has shown that the Nav1.7 channel is also involved in acquired inflammatory pain

This work was supported in part by the Department of Veterans Administration and The Erythromelalgia Association.
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