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January 8, 1999 ANESTHESIA RESEARCH Findings Suggest New Approaches To Easing Chronic Pain Their tips immersed in an acidic soup caused by chronic inflammation, delicate sensory neurons of arthritis patients continuously signal: pain, pain, pain. Traumatized nerves, such as those damaged in an accident, manage to ignore their own injury and telegraph a similar message to the central nervous system, one that results in an unrelenting burning, drilling, or stinging. A sodium channel Clifford Woolf found may prove to be a new drug target for treating pain. People with chronic pain try to adapt and cope using drugs that often are ineffective or dull the pain at the cost of side effects. "Treatments so far are not satisfactory," says Clifford Woolf, the Richard J. Kitz professor of anesthesia research at HMS and MGH. "The mechanisms are not fully understood." In aiming for a mechanistic understanding of pain, Woolf and his colleagues have discovered a new sodium channel, SNS2, specific to the smallest pain-signaling sensory neurons, an obvious switch that may be used to turn off chronic pain. They report their finding in the December Nature Neuroscience. "It could lead to a treatment that would only block pain and not alter other sensations or motor function," Woolf says. Enabling Drug Design Such a drug would tuck into a pocket somewhere along the newly discovered sodium channel, a string of 1,700 amino acids that zigzags across the nerve cell membrane six times. Just one of these amino acids distinguishes the new channel enough from others to make it an attractive target for drug development, says Michael Costigan, a postdoctoral researcher in Woolf's Neural Plasticity Research lab. "The real advance is finding that SNS2 only exists in pain transmitting neurons." Already, researchers at the British company Glaxo-Wellcome have started sifting through their chemical libraries in search of molecules that might selectively block the newly described channel. The sodium channel blocking drugs now available for treating pain tend to target all nerves, affecting even those that have nothing to do with pain and acting on cells responsible for maintaining a normal heartbeat. Another option, Woolf says, are opiates; however, they generate unwelcome side effects as well since opiate receptors exist on both pain- and non-pain-signaling neurons. The newest nonsteroidal anti-inflammatory drugs, COX2 inhibitors, will ease the pain of inflammation with less risk of bleeding or other complications, he says, but inflammation only causes a portion of chronic pain. These drugs will do little for people with nerve damage caused by injury or compression of spinal nerves, metabolic diseases like diabetes, or infectious diseases such as AIDS. Dissecting the molecular workings of pain helps to explain how people with chronic pain can become so sensitive that they may feel a gentle touch as if it were a cigarette being ground into the skin.Their nervous system functions in a state of "exquisite sensitivity" and reacts to the slightest stimuli, Woolf says. The system reaches that state when the pain-signaling nerves have been damaged or when an inflammatory condition such as arthritis swamps their sensory receptors in a soup of chemicals. These chemicals alter nerve function in the periphery and control gene transcription to increase the expression of ion channels such as SNS2. --Cassie Ferguson Diagnosing the Molecular Causes of Pain "There is no such thing as a particular disease-based pain," asserts Clifford Woolf, the Richard J. Kitz professor of anesthesia research at HMS and MGH. "It is not useful by itself to identify pain as cancer pain, pain of postherpetic neuralgia, or low back pain." Instead, he believes pain should be classified by mechanism since different diseases may share mechanisms. The reverse is also true: the same disease may cause pain by different mechanisms. He suggests that pain should be identified by specific details such as the opening and closing of ion channels, the release of transmitters, or the formation of new synaptic contacts. This would allow clinicians to tailor treatment to the specific mechanism and would provide scientists with an objective measure of agony. Pain is now measured in terms of its cause, how long it has lasted, and what part of the body it affects. While stubbing a toe creates an obvious and easily treatable pain, the chronic ache of diabetic neuropathy or arthritis tends to be more elusive. And the subjective nature of pain eludes researchers attempts to quantify it, Woolf says. Classifying pain by mechanism means that along with the traditional questions, a clinician would also try to find out how sensitized the neurons are, whether the sympathetic nervous system is involved, and what role the central nervous system plays. The answers would create a more accurate description of the problem than the simplistic diagnosis of something like "chronic pain due to nerve injury." Depending on the mechanism, doctors could prescribe specific treatments or perhaps a combination of drugs, surgery, and physical therapy in a way analogous to how cardiologists administer cocktails of drugs to treat the combination of problems leading to heart failure.