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Changing Channels

Blocking the capsaicin receptor prevents pain neurons from firing in the first place, but ion channels that help transmit pain signals could also prove good drug targets. Once a pain receptor like the capsaicin receptor is activated, the initial electrical spike causes sodium ion channels to open in sequence down the length of the nerve, conveying the electrical impulse all the way to the nerve’s end. But this sequential opening happens throughout the nervous system, not just in nerves that signal pain. Local anesthetics, in fact, block sodium ion channels, but do so indiscriminately, thus eliminating all nerve activity. Given orally or injected into the bloodstream, local anesthetics would cause paralysis and death.

A dozen sodium ion channels have been identified. But a second sea creature clued researchers into a sodium ion channel found only on pain-sensing nerves. Like the marine snail, the deadly Puffer fish, or blowfish, uses a toxin to kill its prey; this toxin works by blocking sodium channels-with the exception of the channel unique to pain fibers. In 1996 John Wood of University College London and John Hunter at Roche Bioscience simultaneously isolated that channel by relying on its unique resistance to the blowfish toxin.

Target just this sodium channel, researchers assume, and you take out only pain, leaving other nerves free to fire away, happily transmitting impulses all the way to the brain. “It looks like you will get good analgesia in the absence of side effects,” says Phil Birch, chief scientific officer of Ionix Pharmaceuticals in Cambridge, England. Ionix, cofounded by Wood, has found several drug candidates that block the sodium channel and hopes to try one in humans by 2005. “Because the target is expressed only in pain-sensing nerves, [we] can develop a selective blocker,” Birch says. “We think it’ll have a fantastic profile.”

Merck, GlaxoSmithKline, and Elan are also targeting this ion channel. “It’s localized perfectly for where you want to block the pain signals,” says Elan’s Miljanich. Compounds that inhibit it could treat acute and inflammatory pain, such as that caused by arthritis. But even more alluring is neuropathic pain. Nerves damaged by disease seem to have more of these channels, exacerbating the uncontrolled nerve firing of neuropathic pain-pain disconnected from any external injury. Even the best available drug only helps about 30 percent of patients with neuropathic pain. Selective sodium channel blockers could be the first effective drugs deliberately designed to treat their condition.

No one is yet sure they’ll work. “In theory, it’s a wonderful idea,” says Wendye Robbins, a Stanford University pain specialist. “In practice [it’s] more complicated.” Other sodium channels look virtually identical, so it’s hard to target just one. For example, a similar sodium ion channel regulates electrical impulses in the heart, and shutting down sodium channels in the brain would cause stupor. Ionix says its molecules do not block these channels, but the ultimate test will be in humans.

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Tagged: Biomedicine

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