Science News - June 30, 2012

Outside cell Inside cell

Channel changes Mutations in a gene called SCN9A can cause a number of pain disorders (right). this gene carries the instructions for an elaborate protein called nav1.7 (above) that lets sodium ions pass into a nerve cell. Boxes show locations where SCN9A mutations linked to different disorders alter the protein.

Nav1.7-linked pain syndrome Examples of symptoms

Small fiber neuropathy Hypersensitivity to stimuli; red, painful extremities
Inherited erythromelalgia Extremities become red, painful and swollen
Paroxysmal extreme pain disorder Stabbing pain in the rectum, genitalia, eyes, jaw and limbs
Congenital indifference to pain An absence of the sensation of pain
SourCES: S. DIB-HAJJ E T AL/ TRENDS IN NEUROSCIENCES 2007 AnD I. MErkIES/MAAStrICHt unIv. MEDICAl CEntEr

Pain, pain, go away

The efforts of nearly two decades of research on Nav1.7 are now bearing fruit. London-based Convergence Pharmaceuticals has developed a compound that blocks the channel only when nerves are firing like crazy. Normal pain thresholds, such as those experienced when touching a hot stove, aren’t altered by the Nav1.7 blocker, says Simon Tate, Convergence’s chief scientific officer. The company’s compound is now in Phase II clinical testing — the stage that looks at dosage and effectiveness — for a painful condition of the lower back and limbs called lumbosacral radiculopathy. Convergence has also started a Phase II trial testing the same Nav1.7 blocker as a treatment for trigeminal neuralgia, a chronic pain condition that entails recurring brief episodes of intense, stabbing facial pain.

In January the Canadian company Xenon Pharmaceuticals reported success with an Nav1.7 blocker for treating erythromelalgia, often referred to as “man on fire syndrome.” And Pfizer and its subsidiary Icagen are working with Waxman and Yale colleague Sulayman Dib-Hajj to investigate a blocker for treating the same disorder.

Some conditions under investigation — lumbosacral radiculopathy and trigeminal neuralgia, for example — aren’t caused by inherited mutations, but appear to result from nerve damage. If an Nav1.7 blocker works in such cases, the target may prove useful for treating long-term debilitating pain more broadly. Good candidates may include the 60 to 70 percent of

people with diabetes who have nervous system damage that can cause daily pain. People with traumatic injuries for which the healing time is long, such as a severe burn, may also benefit. Studies by Waxman and colleagues have found that mice without working Nav1.7 channels don’t develop the hypersensitivity to heat that typically follows a burn injury.

Beyond offering new tricks for treating pain when it strikes, studying the channel may also help doctors understand their patients’ personal pain profiles. Recent research led by Woods found that some versions of SCN9A in people without known pain disorders can confer increased sensitivity to pain. Such studies may help explain why one solider who has been shot through the arm experiences chronic post-trauma pain, while another soldier with the same wound might not. Or why some amputees have phantom limb pain and others don’t, says Waxman.

“It’s very exciting to us,” he says.
“If you go into a room full of people
who all look normal, 30 percent may
have a lower threshold for pain and an
increased likelihood of developing pain
after nerve injury.”
As scientists continue to investigate
the nuances of Nav1.7, some are turning
to its channel brethren as well. Nav1.8
and Nav1.9, also sodium channels, are
less understood than Nav1.7. But sci-
entists do know that these channels
also play a role in generating pain, and
therefore may be promising targets too,
says Michael Costigan, a specialist in
the genetics of chronic pain at Boston
Children’s Hospital. Changes in the
behavior of Nav1.8 have been implicated
in inflammatory pain, for instance.