Getting at the Molecular Roots of Pain

to eliminate difficult-to-control pain while leaving normal sensation intact. Pain is a part of life. Often, a few painkillers and some rest are enough to soothe the scraped knees of childhood and the aches and sprains of adulthood. But for some, pain is not as fleeting or as easily dismissed. The pain from cancer, chemotherapy, arthritis, AIDS, and other diseases can be unrelenting and incapacitating. Some individuals even experience constant, bone-crushing pain for no apparent reason. For many of these chronic pain sufferers, even morphine doesn't relieve the agony. How is it that some types of pain--caused by a twisted ankle or a nasty sunburn--are temporary and can be subdued by painkillers, while others are persistent and seemingly untreatable? To answer that question, researchers in the laboratory and the clinic are probing the mechanisms that underlie both acute and chronic pain. Their search may yield new methods for eliminating difficult-to-control pain while leaving normal sensation intact. IDENTIFYING PAIN'S DESTINATION: The key to understanding pain may lie in identifying the proper molecular targets, says Lorne Mendell of the State University of New York in Stony Brook. The key may lie in identifying the proper molecular targets, says Lorne Mendell of the State University of New York in Stony Brook. In the past few years, scientists have discovered a number of ion channels that activate pain-sensing neurons and a handful of receptors that respond to either pain-inducing signals or to pain-relieving analgesics. Some of these channels and receptors appear to be unique to the neurons that transmit pain messages from a paper-cut pinkie finger through the spinal cord and into the brain. Such specificity makes these molecules excellent targets for selective analgesics that might block prolonged pain signals without causing unpleasant side effects. And last month, at a special National Academy of Sciences-sponsored colloquium on the neurobiology of pain to be held in Irvine, scientists from pharmaceutical companies and academia gathered to share their findings and discuss the recent progress they have made in understanding the mechanisms of pain. To stop pain in its tracks, it seems reasonable to attack it at its source: the neurons that sense noxious stimuli. Stub a toe or burn a finger and a set of specialized neurons--called nociceptors--sends a message about "pain in the periphery" to the spinal cord. There a second set of neurons relays the information "north" to the brain stem, the thalamus, and eventually to the cerebral cortex--which analyzes the message and subsequently prompts that indignant yelp of "ouch." COUNTERING PAIN: Although using capsaicin to eliminate pain might seem counterintuitive, it actually makes sense, says Jon Levine of the University of California, San Francisco. Pain-sensing neurons are the first link in the pain chain, so some researchers are exploring how these specialized neurons detect painful stimuli. Their talent may stem, at least in part, from their capsaicin receptors. Capsaicin is the molecule that gives chili peppers their fiery zing. Last year, researchers led by David Julius and Jon Levine of the University of California, San Francisco (UCSF), cloned the capsaicin receptor--found exclusively in pain- processing neurons.1 Studying how the receptor is activated will be useful, says Mendell, because "the closer you get to the stimulus, the easier it is to figure out the individual molecular steps that lead to the production of a nociceptive signal." When capsaicin binds to its receptor, it opens a channel and excites the neuron, which then transmits its pain signal. The same receptors are also located on neurons that are activated by heat--hence the burning sensation associated with a mouthful of hot chili peppers. Stimulate capsaicin receptors and a pain message is born. Such pain is a normal response--and will probably stop you from rubbing your eyes next time you handle jalapeños. But what happens when you get sunburn? The area becomes exquisitely tender and it hurts to touch it even lightly. This exaggerated sensitivity--called sensitization--primes the pain pump and causes neurons in the pain pathway to overreact to painful and sometimes nonpainful stimuli. The process, triggered by inflammation or tissue injury, is mediated in part by nerve growth factor (NGF), which causes pain-sensing neurons to react more vigorously to noxious stimuli, says Mendell. In fact, NGF may enhance the response of sensory neurons by boosting the activity of the capsaicin receptor, a finding that Mendell and X. Q. Shu presented at the November meeting of the Society for Neuroscience. If researchers can figure out how to disable the capsaicin receptor, they might be able to stop pain messages before they start. Which is what Levine, Wendye Robbins, and their UCSF colleagues have now done--using large doses of capsaicin itself. The researchers found that overstimulating the receptor can actually reduce clinical pain, perhaps by killing off the sensitive tips of these neurons by overexciting them. The researchers treated people with chronic pain with high concentrations of capsaicin--5 percent to 10 percent solutions. (To provide some perspective, sporting goods stores market 1 percent capsaicin solutions as a grizzly bear repellent.) Robbins, an anesthesiologist by trade, administered a local anesthetic before brushing capsaicin onto the patients' skin to minimize the burning sensation. The results, says Levine, were "extremely dramatic." Of the 10 patients treated, nine experienced a substantial reduction in pain--an effect that in some cases lasted for months.2 Although using capsaicin to eliminate pain might seem counterintuitive, Levine says it actually makes sense. Think about eating lots of spicy food. "After awhile, you can eat foods that previously you couldn't get near your mouth without reaching for a glass of water," he says. With continued stimulation, the painful sensation diminishes. Of course, eliminating all pain is not the goal, says Mendell. "Nobody thinks that if you step on a nail you shouldn't feel pain," he notes. And people treated with capsaicin still feel acute pain, says Levine. "If you stick them with a pin or pinch them, they feel it," he notes. What they don't feel is the chronic, nagging pain that even morphine couldn't touch. REACHING OUT: Bridging basic and clinical science is a part of the Pain Center's mission at the University of Maryland and Johns Hopkins University in Baltimore, explains Ron Dubner of UM. But the capsaicin receptor is not the only exciting target molecule for potentially specific analgesics. Pain-sensing neurons also express a unique type of sodium channel. Sodium channels, in general, control the excitability of neurons all over the body--in the heart, the gut, and the nervous system. But the sodium channel found almost exclusively in small-diameter pain-sensing neurons--identified by John Wood and his colleagues at the University College of London and independently by John Hunter and his colleagues at Roche Bioscience in Palo Alto--is unusual in that it is resistant to tetrodotoxin (TTX), a neurotoxin from puffer fish that disables many other sodium channels.3,4 The new TTX-resistant channel--dubbed PN3 by the Roche researchers--is definitely involved in transmitting and sensitizing animals to pain signals, says Kathleen Gogas of Roche. She and her colleagues have examined the distribution of PN3 in neurons following nerve injury in rats--a model for human neuropathic pain. They found that the channel accumulates at the point of injury.5 "At the site of damage, PN3 is everywhere," says Gogas. In terms of sensitization, perhaps the redistribution changes the sensitivity of the neuron, causing it to respond inappropriately to stimuli that would normally not be considered painful. Roche and other pharmaceutical companies are now searching for inhibitors that will selectively block the activation of this TTX-resistant sodium channel, leaving the TTX-sensitive channels in the brain and heart and gut functioning normally. Whether anyone has found such a drug remains a closely guarded secret. In the meantime, PN3 has been joined by SNS2--a second TTX-resistant sodium channel. Clifford Woolf and his colleagues at the Massachusetts General Hospital in Charlestown, in collaboration with researchers at Glaxo Wellcome in England, report that this new sodium channel--unlike PN3--is found exclusively in pain neurons.6 What its role is he doesn't yet know. "Right now we know that SNS2 is expressed in sensory neurons along with PN3 and other sodium channels," says Woolf. "Whether it has a specific role in pain transmission, we need to find out." Because SNS2 is located only in pain-sensing neurons, inhibiting the channel should alleviate pain without causing unwanted side effects in the central nervous system or heart. But which channel--PN3 or SNS2--would make the better target? Right now it's hard to know, says Woolf. "Maybe they're redundant. Or maybe they work together," he says. Woolf and others are currently attempting to make a knockout mouse, lacking one or both genes, to determine which if either channel might be central to pain transmission. WITHOUT LOSS OF SENSATION: A signaling molecule called protein kinase C appears to be involved in lessening pain without losing normal feeling, according to UCSF's Allan Basbaum. Another knockout mouse that may lead the way to better treatments for chronic pain was generated last year by Allan Basbaum of UCSF and Susumu Tonegawa, a Nobel laureate and Howard Hughes Medical Institute investigator at the Massachusetts Institute of Technology. The genetically engineered mouse lacks a particular form of a signaling molecule called protein kinase C (PKC). Basbaum and his colleagues had reasoned that when neurons carrying pain messages are excited, their channels open and calcium floods into the cells. Calcium influx switches on intracellular signaling cascades that activate the molecules--including PKC gamma--that transmit pain's signal. Eliminate or block PKC, and pain might be stanched. CARRYING THROUGH: Molecular finds need to be pursued in whole animals and eventually patients to put them in context with the physiology of the system, says Gerald Gebhart of the University of Iowa. The results look promising, says Basbaum. It turns out that mice without PKC gamma respond normally to acute pain: PKC-deficient mice will lift their paws off a hot surface as quickly as normal mice do. Which is good, he explains, "because you don't want to develop a drug that will block normal pain." But the mice fail to develop the neuropathic pain syndrome seen in normal mice when their sciatic nerves are injured.7 What's even more exciting for developing novel analgesics, says Basbaum, is that PKC gamma appears to be found exclusively in interneurons involved in pain processing in the spinal cord. Of course, these molecular finds need to be pursued in whole animals and eventually patients. "Discovering new channels is fine," says Gerald Gebhart of the University of Iowa, who is working on characterizing a novel kappa opiate receptor found in the gut. "But you need to put the molecules into context within the system. You need to go back to animals and look at physiology." Levine agrees. "Basic and clinical science have to talk to one another," he says. "Findings need to be taken from the bench to the bed and back again." Bridging basic and clinical science is, in part, the mission of a regional Pain Center that draws on the expertise of researchers at the University of Maryland and Johns Hopkins University in Baltimore, says Ron Dubner of the University of Maryland, the Center's program director. To get information on pain research and management out to physicians and to the public, the Center plans to conduct outreach programs in the inner city and suburbs of Baltimore. Education for patients and physicians is essential. "Doctors need to learn how to treat pain," says Basbaum, who worries that not enough physicians realize how debilitating pain can be. Only 60 oncologists belong to the 7,000-member International Association for the Study of Pain. The problem? "Pain can't be seen," he says. Perhaps understanding the roots of pain will help researchers and clinicians devise more effective treatments. "Pain is not just a symptom," notes Basbaum. "It is a disease." Advocacy GroupsAmerican Pain Foundation 111 S. Calvert St., Suite 2700Baltimore, MD 21202410-385-5276 American Chronic Pain AssociationP.O. Box 850 Rocklin, CA 95677916-632-0922www.theacpa.org National Pain Outreach CenterP.O. Box 274Millsboro, VA 24460540-997-5004www.chronicpain.org (Avail. 1/99) TMJ AssociationP.O. Box 26770Milwaukee, WI 53226414-259-3223www.tmj.orgProfessional Organizations American Pain Society4700 West Lake Ave.Glenview, IL 60025847-375-4715www.ampainsoc.org International Association for the Study of Pain (Seattle)909 N.E. 43rd St., Suite 306Seattle, WA 98105206-547-6409 www.halcyon.com/iasp Karen Hopkin is a freelance science writer based in Silver Spring, Md. M.J. Caterina et al., "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature, 389:816-24, 1997. W.R. Robbins et al., "Treatment of intractable pain with topical large-dose capsaicin: Preliminary reports," Anesthesia and Analgesia, 86:579-83, March 1998. A.N. Akopian et al., "A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons," Nature, 379:257-62, 1996. L. Sangameswaran et al., "Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons," Journal of Biological Chemistry, 271:953-6, 1996. S.D. Novakovic et al., "Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions," Journal of Neuroscience, 18:2174-87, March 15, 1998. S. Tate et al., "Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons," Nature Neuroscience, 1:653-5, December 1998. A.B. Malmberg et al., "Preserved acute pain and reduced neuropathic pain in mice lacking PKC gamma," Science, 278:279-83, 1997.

Getting at the Molecular Roots of Pain

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