Different mutations in a single gene, SCN9A, demonstrate how much about pain remains mysterious.

In recent years, rigorous research has provided scientists with a detailed understanding of how pain signals travel from the skin and other organs to the brain. Different mutations in a single gene, however, demonstrate how much about pain remains mysterious: one worsens pain, while a second seems to prevent it. The gene, known as SCN9A, produces a protein called Nav1.7, one of ten proteins that make up the sodium channels that dot the surface of axons and help propagate neural signals. Nav1.7 is found in specialized sensory fibers that respond to pain signals from throughout the body and transmit them to the spinal cord and brain. Stephen G. Waxman, chairman of neurology at Yale, recently demonstrated that a mutation in SCN9A is responsible for hereditary erythromelalgia, a form of chronic and excruciating pain that causes the feet and other extremities to turn bright red when they become warm. Some people with this disorder cannot bear to wear shoes, for example, because the trapped heat brings on the pain. Some relieve the pain by soaking their feet in ice water. Waxman and his team traced erythromelalgia to a mutation that affects Nav1.7 and causes sodium channels to open too easily, allowing an excessive influx of pain-causing sodium ions, and to close too sluggishly, allowing the pain impulse to linger. However, a different mutation in SCN9A has scientists scratching their heads. This mutation has been shown to prevent people from experiencing any form of pain at all. Pain-Free in Pakistan Cambridge professor C. Geoffrey Woods and colleagues studied members of a family in northern Pakistan who apparently have never experienced pain and suffer an array of injuries as a result. The researchers were alerted to this disorder by stories of a boy who did street performances during which he would push the blade of a knife painlessly through his arm, or walk on burning coals. Before they could meet the boy, the researchers learned he had died shortly before his 14th birthday; he had jumped off the roof of a house while showing off for friends. But researchers did locate members of the boy’s extended family who have the same condition. Most have severe scars from chewing their lips and tongue during childhood. Most have suffered broken bones, recognized only when they started limping painlessly or lost the ability to move one arm. Yet they appear to have normal sensation in every other way. They can distinguish warm food and drink from cold, for example, although most suffered severe scalding as children while eating. What makes this condition even more perplexing is that mice bred with the Pakistani family’s mutation all die. The Nav1.7 protein is found both in nerves that sense pain and in sympathetic nerves that control autonomic bodily functions such as pupil dilation and heart rate. “If extrapolated to humans, one might expect sympathetic dysfunction resulting in lethality … but these people didn’t appear to have sympathetic dysfunction,” Waxman says. “The fact that these patients actually exist makes it an intriguing and instructive scientific story.” The sensation we call pain is produced when pressure, heat, inflammation or some other noxious stimulus depolarizes receptors in the skin and other organs that send pain signals to the spinal cord and brain. Because pain signals follow their own pathways to the brain, the family members in Pakistan are able to perceive nonpainful sensations normally. When the sensation would become painful to most people, they continue to perceive it as normal because their pain pathways are inoperative. “There are different classes of neurons that are selectively tuned to detect painfully cold versus nonpainfully cool versus nonpainfully warm versus painfully hot temperatures, just as there are different classes of neurons that respond to lightly touching the skin versus pinching the skin,” says Michael Caterina of the Johns Hopkins University School of Medicine. “To accomplish such discrimination, each of these classes of neurons with their particular response properties is connected to a different set of pathways leading to the brain.” Certain other genetic defects leave people without any pain pathways in their body whatsoever, which makes their lack of pain perception easy to understand. The lack of pain in people with the SCN9A mutation, however, is much harder to explain, says Clifford Woolf, a professor of anesthesia research at Massachusetts General Hospital. “That a single loss-of-function mutation in a single gene for a single sodium channel could produce this total loss of pain sensation is very surprising and, frankly, inexplicable,” Woolf says. “They have just a single channel missing—other channels should be there. From what we know of the electrophysiology of the membrane, these other channels should be able to conduct and activate cells. They should still function.” Genes, Expectations Affect Pain Pain is not an objective, mechanical response to harmful stimuli. On the contrary, genetic differences cause significant variation in the amount of pain that people can tolerate. One study, for example, found that a common genetic variation affecting the metabolism of dopamine, adrenaline and other molecules significantly altered the perception of pain, presumably by increasing or decreasing the amount of opioids, natural opiate-like chemicals produced in the brain. Another study found that a variation in the gene for a receptor found abundantly in people with red hair and fair skin produced a reduced sensitivity to pain in women, and increased pain relief from opioids. Last fall, researchers led by Woolf reported in Nature Medicine that a gene for an enzyme called GTP cyclohydrolase helps control the production of various molecules such as serotonin and a widespread chemical messenger known as nitric oxide. They suspect this gene contributes to the susceptibility of some people to chronic neuropathic pain, produced inappropriately by the body even in the absence of harmful stimuli. A person’s emotional makeup and expectations also modulate pain. A study by Tracy Hampton in the Nov. 22/29, 2006, Journal of the American Medical Association, for example, reported the case of a man who arrived at the emergency room writhing in pain with a long nail through his boot. When doctors showed him that the nail had passed harmlessly between his toes, his pain disappeared. Conversely, people who are grievously injured—a soldier on the battlefield who has been shot, for example, or a person who runs through a wall of fire to escape a burning building—often feel no pain until the crisis has passed. Simple distraction has been shown to reduce the amount of pain a person experiences. Breathing exercises women learn before childbirth are designed primarily to distract them from the pain of contractions. Functional magnetic resonance imaging scans have shown that activity in the pain-inhibiting regions of the brain increased significantly when the subject was distracted from the painful stimulus. On the other hand, people who experience chronic pain, especially neuropathic pain produced by malfunctioning pain receptors rather than an obvious injury, often develop anxiety that causes them to focus intensively on their pain. As a result, they often are told the pain is all in their head. But brain scans and other forms of brain imaging have revealed distinctive signatures for pain in the somatosensory cortex, the anterior cingulate cortex, and the prefrontal cortex. Counting pain sensors in the skin also is emerging as a way of providing an objective measure of pain sensitivity (see “Fewer Sensors, More Pain”). Drug Possibilities The pain-free family in Pakistan have sodium channels in their pain receptors, but those channels are inactive because of the mutation affecting the Nav1.7 protein. Therefore, a drug that blocks those channels should provide pain relief. But the sodium channels would have to be blocked very selectively. “If you block all sodium channels, you’re dead,” says David Julius of the University of California, San Francisco, who studies the molecular basis of the sense of touch. “What kills people who die from eating puffer fish is a toxin called tetrodotoxin, which blocks voltage-gated sodium channels.” Researchers are heartened by rumors of innovative drugs in development that can selectively block the Nav1.7 sodium channel and alleviate pain. John N. Wood of University College London, one of the authors of the paper about the mutation found among members of the Pakistani family, believes that Nav1.7 may be the electrical switch that initiates the sense of pain. “A drug that blocks this channel specifically would be an excellent analgesic,” he says.

pain, gene, SCN9A, brain, sensation, Nav1.7