Pain Research Comes into Its Own

In the first case of its kind, a jury earlier this year found a physician guilty of undermedicating a patient for pain. Claiming that such an action amounted to elder abuse and recklessness, the judge awarded $1.5 million to the patient's family. The precedent-setting case occurred after the passage of a Congressional provision, the Decade of Pain Control and Research, which went into effect Jan. 1. Signed into law by then-President Bill Clinton and sponsored by the American Academy of Pain Medicine, this mandate is intended to stimulate progress into pain research, education, and clinical management. "Too many people with chronic pain are undertreated," says neuroscientist Allan I. Basbaum, department of anatomy chairman and member of the Keck Center for Integrative Neuroscience at the University of California, San Francisco. "Pain is difficult to measure. You can't see it and thus the medical community often underestimates the magnitude of a patient's pain. And because people die in pain, but not of pain, nobody wants to give money specifically to pain research." Editor's Note: This is the fourth article in a series on the senses. The final installment, on the sense of smell, will be published in the December 10 issue. Private foundation funds for pain research remain scant, but National Institutes of Health funding--partly in response to the congressional mandate--has become more abundant spending. According to NIH numbers, the 1995 FY budget for pain condition was $67.3 million, the 2002 FY budget is estimated at $157.1 million. It has also increased because of a slew of high-profile reports published in recent years that begin to elucidate the molecular biology of pain. Currently, commonly used pain treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates do not work specifically on pain itself. Instead, the drugs act both on the pain pathway's receptors and the identical receptors outside of the pain pathway, and they can cause unwanted side effects and dependence. Research has focused on nociceptors, primary afferent neurons that specifically respond to noxious thermal, chemical, or mechanical stimuli. Pain-triggering ion channels are believed to provide nociceptors their distinct sensory properties. Identified in just the past few years, ion channels such as VR1, P2X3, and TTX-resistant sodium channels represent promising targets for highly selective local anesthetics and analgesics for treating a variety of clinical pain conditions, according to Basbaum. "If you develop a drug to block them, the likelihood is that the side effects are going to be reduced," he says. Opening the Door on Pain Pathway In 1997, UC-San Francisco researchers, led by David Julius, cloned one of the first pain-specific ion channel proteins.1 Called VR1 (vanilloid receptor type-1), this receptor protein binds the capsaicin molecule in peppers and sets off a burning sensation. This was widely recognized as an important step because no one before had molecularly identified how capsaicin targets a heat-sensing nociceptor and activates the pain signal. Last year, Julius' group created a mouse model lacking the gene that produces VR1.2 The mouse showed no preference between water laced with capsaicin and plain water, and also tolerated painful heat. Lacking the VR1 receptor didn't completely erase response to thermal pain, though, indicating that more than one chemical process is involved in pain. Another chemical process that may be involved here is a receptor called VRL-1 (vanilloid receptor like subtype 1). Identified by Julius' group in 1999, VRL-1 is structurally related to VR1, but it does not respond to capsaicin, acid, or moderate heat. Instead, high temperatures activate it; its threshold is approximately 52°C. Comparatively, the VR1 threshold is a more moderate 43°C.3 How Immediate Pain Becomes Chronic Today, pain field research has shifted from acute nociception--how people initially respond to noxious stimuli like capsaicin and ATP--to chronic nociception, how inflammation develops and how the nervous system responds to it. Changes occur in the nervous system that trigger a switch; pain that begins as acute and temporary, such as that from a pinprick, becomes chronic, like a severe sunburn pain, says Julius. His team is focusing on this change's molecular components. "This switch in the central nervous system is clearly a very important component of chronic pain development," Julius says. At the site of an injury, such as an infection or a wound, nerve growth factors and glial-derived neurotrophin factors make the injured tissue acidic, explains Julius. The combination of these different factors, known as the inflammatory soup, has the effect of making pain-sensing neurons more sensitive to stimuli. So to sunburned skin, for example, a gentle slap on the back is painful and a warm shower is unbearably hot. This is because the sensitivity threshold readjusts to a lower threshold called hyperalgesia. At least part of the action that initiates this change probably occurs through the initial sensitization of the nerve terminals, Julius says. The inflammatory soup may actually boost the capsaicin receptor's activity. So, Julius is examining how the VR1 channel is regulated by factors produced during injury, such as the different components of the inflammatory soup. He has found that VR1 is a target for sensitization changes and that at some level, a change occurs in the channel's ability to be activated by heat, making activation easier. In recent research, his group has found that once a mouse is injured by heat, its tolerance for heat stimuli drops from about 42°C degrees to about 35°C. Notably, mice engineered to lack VR1 did not develop sensitization. "We're trying to tie to together the behavioral studies with the cellular studies to understand the molecule-to-molecule signaling that leads to sensitization," Julius says. But VR1 is not the only promising target for blocking chronic pain. Others have been identified, among them a voltage-gated sodium ion channel expressed only by nociceptors. The sodium channel is unusual in that it resists tetrodotoxin (TTX), a neurotoxin from puffer fish that disables most sodium channels. Recently, Michael S. Gold, from the department of oral and craniofacial biological sciences at the University of Maryland, and his group demonstrated the role of this TTX-resistant sodium channel in the initiation of inflammatory hyperalgesia. Gold suggests that one way to attenuate inflammatory pain could be to block the TTX-resistant sodium channel. A drug that would inhibit activation of the TTX-resistant sodium channel might block pain while allowing the TTX-sensitive channels in the brain, heart, and gut to function normally. (Of the many sodium channels in the body, only two are known to be TTX-resistant, and both are specific to the pain pathway.) Decreasing, but not completely blocking, the sodium channels are key to successful pain reduction. "If you decrease the channel a little bit, you don't have the ongoing pain," Gold says. "But at the same time, you don't change normal acute pain processing, which is important. If you pick up a hot plate, you want to know how to respond to that." The function of this TTX-resistant sodium channel could be linked to VR1, and together the two channels could be responsible for sensitization. The capsaicin receptor, says Gold, converts outside energy, such as heat, into an electrical signal that the nervous system can use. That electrical signal is then used by the nervous system to rapidly send a pain signal back and forth in the form of an action potential. The sodium channel provides the basis for the action potential. "Some of the molecules released by the body in response to injury may lead to more sensitive sodium channels, or easier activation of sodium channels. And when they become more sensitive, you get more action potentials from the VR1, so you have more pain," Gold says. Now that pain researchers are drawing on the tools of molecular biology, the identification of additional drug targets is likely to continue at a rapid pace, according to researchers. The general view among them, though, is that a new pain medication solely based on blocking pain-causing neurons is unlikely to work against all pain. "There are a lot of different ways that pain can be caused by injury or disease. Different types of channels allow the body to interpret these different types of pain signals," says Sean Cook, a pain researcher at the Vollum Institute at Oregon Health Sciences University. Looking Beyond Nociceptors A recent report suggests, for the first time, that pain may not be mediated solely by the nociceptors. Researchers at the University of Colorado reported that spinal cord glia amplify pain by releasing proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor.4 In turn, the proinflammatory cytokines promote pathological pain, which occurs in infectious diseases such as AIDS, and neuropathic pain, which follows peripheral nerve injury or inflammation. Previously, scientists generally believed that glia played no role in pain because they lack axons and therefore were incapable of cell-to-cell signaling. But now, some researchers believe that glial activation can create, maintain, or expand pain in response to peripheral injury and inflammation, according to Linda R. Watkins, professor in the department of psychology and the Center for Neurosciences at University of Colorado, and the article's lead author. The recent findings suggest a new approach to pain control, because all current clinical therapies are focused on altering neuronal, rather than glial, function, Watkins says. The finding opens a promising new target for pharmacological treatments and may have significant implications for drug development aimed at controlling clinical pain, she says. Pain "is a dynamic process where activated glia interact both with pain messages arriving at the spinal cord and with spinal cord neurons whose job it is to relay that message up to the brain," Watkins says. "This is a whole new level of pain processing [that] promises to expand our understanding not only of pain, but also of glial-neuronal interactions, since there is certainly no reason to believe that pain is the only phenomenon where glial-neuronal interactions will prove to be important." Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor for The Scientist. References 1. M.J. Caterina et al., "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature, 389:816-24, 1997. 2.M.J. Caterina et al., "Impaired nociception and pain sensation in mice lacking the capsaicin receptor, Science, 288:306-13, 2000. 3. M.J. Caterina et al., "A capsaicin-receptor homologue with a high threshold for noxious heat," Nature, 398:436-41, 1999. 4. L.R. Watkins et al., "Glial activation: a driving force for pathological pain, Trends in Neuroscience, 24[8]:450-5, August 2001. Supplemental Materials A schematic of pain and pain modulation (45K)

Pain Research Comes into Its Own

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