When everything works, the pain system triggers behaviors that lead us to flee danger or to rest and recover from an injury. But it doesn’t always work right. In chronic pain, for instance, signaling can become hyperactive so that even the lightest touch hurts or, in extreme cases, electrical signals fire for no apparent reason. Researchers have recently begun to describe how this malfunction, known as central sensitization, makes nociceptor synapses dangerously hyperactive, as occurs in some mysterious and hard-to-treat pain disorders, such as neuropathy, chronic inflammatory pain, and fibromyalgia.

Channeling Pain

Nerve cell ion channels selectively allow the passage of four types of charged atoms: positive ions of sodium, potassium, and calcium, and a negative ion, chloride. The movement of these ions across a membrane creates an electric current that transiently alters the cell’s membrane voltage. The past two decades have seen an avalanche of discoveries of ion channels related to pain sensation.

In the 1990s, Gail Mandel, now an HHMI investigator at the Oregon Health and Science University, and her colleagues Simon Halegoua and Paul Brehm at New York’s Stony Brook University were exploring the variety of sodium-selective channels in mammals. Sodium channels act as molecular amplifiers, turning small electrical signals into action potentials that can conduct for long distances along an axon. In 1997, Mandel discovered a sodium channel, now called Nav1.7, which is abundant on sensory neurons. From the channel’s location and density, the researchers theorized that it plays a role in pain perception.

Human genetic studies strongly support the idea. Erythromelalgia, a rare disease in which patients periodically feel severe burning pain without any sensory stimulus, is caused by a mutation that increases Nav1.7 activity, rendering nociceptors hyperexcitable. Another mutation that diminishes Nav1.7 activity causes a rare disease in which patients are profoundly insensitive to burns and some other kinds of tissue damage. A few pharmaceutical companies are testing compounds to control Nav1.7 as a way to suppress pain.

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The same year that Mandel’s group found the sodium channel, Julius and colleagues published findings about pain perception emanating from one among a subfamily of ion channels called transient receptor-potential vanilloid (TRPV, called “trip-vee”) channels. Julius used capsaicin to demonstrate that burning heat specifically activates the TRPV channel in peripheral nociceptors. That discovery also provided a model for future pain studies using natural ingredients to simulate painful stimuli, opening the door to a host of other findings.

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