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ANESTHESIA Pain Promoter Plays Unexpected Role in Central Nervous SystemDiscovery Could Lead to More Effective Painkillers Pain—like its kinder counterpart, pleasure—occurs in various forms and with diverse consequences. The sting of burning pavement or a splinter under a bare foot is intense but brief, prompting an action that puts an end to the suffering. The throb of a surgical wound or infected ear, on the other hand, lasts for hours, days, and even weeks. Rather than a call to act, such pain is often incapacitating. For years researchers believed that this second longer-lasting pain was due to changes near the site of injury or infection. In the inflammatory melee following such assaults, it was thought, immune cells produce a sensitizing substance that keeps local pain fibers in a state of high alert—turning them, in effect, into a "Do not disturb" sign for the affected area.
Inflammatory pain is the result of sensitization in the central nervous system, not just at the periphery as generally believed. In addition to triggering the sensitization of pain fiber terminals (black pathway), inflammatory cells at the site of injury or infection may produce a signal that gets into the central nervous system, inducing IL-1 beta and Cox-2 expression (red pathway). Cox-2 induces prostaglandin E2 (PGE2), which sensitizes neurons in the central nervous system, making them more responsive to input and more likely to send pain signals to the brain. Illustration by Jeff Cleary The Bigger PictureThis localized view, it now appears, is myopic. Clifford Woolf, the Richard J. Kitz professor of anesthesia research at Massachusetts General Hospital, and his colleagues have found that during inflammation, the enzyme that produces the sensitizing signal is released not just at the site of injury but throughout the central nervous system.The research team, led by Tarek Samad, research fellow in anesthesia, administered inflammatory wounds to the hind limbs of rats and found that the enzyme cyclooxygenase-2 (Cox-2), and its product, prostaglandin E2 (PGE2), were expressed in the spinal cord and the brain of the animals. By lowering levels of centrally produced Cox-2, they could decrease sensitivity to painful stimuli in the animals. The findings, which are reported in the March 22 Nature, upset ideas not just about the mechanism of persistent pain but also its treatment. Standard drugs like aspirin, ibuprofen, and naproxen are thought to quell pain by inhibiting Cox-2 at the site of inflammation. The new findings suggest that the drugs may act on the central nervous system, that is, if they are capable of crossing the blood–brain barrier.
Clifford Woolf and his colleagues have discovered that during inflammatory pain, the enzyme Cox-2 produces a sensitizing signal in the central nervous system as well as at the site of injury. Photo by Graham Ramsay "We need to see if existing drugs do enter the brain, and if they don't, the pharmaceutical industry needs to get its act together because there's enormous potential here to improve the efficacy of such drugs," Woolf said. Delivering Cox-2–inhibiting agents directly into the brain—and only the brain—could also be a strategy for alleviating the side effects of aspirin and other conventional painkillers. Because these drugs inhibit all forms of Cox, including Cox-1, which is normally produced in the stomach and platelets, they can lead to stomach upset, ulcers, and blood thinning. Newer drugs such as celecoxib (Celebrex) and rofecoxib(Vioxx), which target only Cox-2, produce fewer side effects. Woolf believes that even these painkillers may be enhanced by delivery to the central nervous system. "If these drugs don't cross into the brain, or they don't do it well or do it slowly, then increasing the penetrance would increase their efficiency quite considerably," he said. New PriorityDespite all the attention it draws in patients, pain has only in recent years been deemed a subject worthy of scientific scrutiny. "It really was the Cinderella of medicine," said Woolf. "Pain was always seen as part of some other problem, whether it's orthopedic or gastrointestinal or whatever." Woolf's own efforts for the past 20 years have been directed toward understanding how pain signals in the periphery—for example, at the site of a wound or infection—are received and interpreted by neurons in the spinal cord.Several years ago, he and his colleagues made the first of a series of surprising discoveries. Working in rats, they found that by increasing synaptic input to the spinal cord neurons, they could render those neurons abnormally sensitive. "The traditional view was that the spinal cord and pathway to the cortex were like a passive telephone line," he said. Suspecting that the spinal cord neurons might be responding to something in addition to synaptic activity, Samad, Woolf, and their colleagues looked in the spinal cord for genes that might be more highly expressed during the pain response. They found that the Cox-2 gene was upregulated—"to our surprise and everybody else's," said Woolf. Cox-2 was known to make PGE2, which sensitizes pain fibers, but this chain of events was thought to occur only in the periphery. "Suddenly we find Cox-2 is produced in the spinal cord," said Woolf. And not only the spinal cord. The researchers found it in the brain stem and thalamus of the animals.
The discovery of Cox-2 in the central nervous system came as a surprise to the research team, which was led by Tarek Samad (far right) and included Andrew Allchorne and Kimberly Moore, research fellows in anesthesia. Photo by Graham Ramsay What's more, the centrally located Cox-2 appeared to produce PGE2. The question remained—what was inducing Cox-2 production in the central nervous system? Increased synaptic activity from the pain fibers was one possibility. But when the activity was blocked, Cox-2 production continued. "We realized there was some other signal," Woolf said. Piecing Together PainIn the periphery, Cox-2 is induced by inflammatory chemicals, including the cytokine interleukin-1 beta (IL-1 beta). Samad and his colleagues checked the animals' bloodstream—the normal carrier of IL-1 beta—and found no sign of the protein. "We thought if it wasn't in the bloodstream, it wouldn't be in the central nervous system," said Woolf. They examined the cerebrospinal fluid of the animals and, to their amazement, found very high levels of the cytokine.To explore the possible role of IL-1 beta, the researchers blocked it. Not only did central Cox-2 production stop in the animals, their sensitivity to pain was greatly lowered. "We think IL-1 beta in the central nervous system is a key trigger that induces Cox-2 expression and therefore causes the pain hypersensitivity," said Woolf. But what is pulling the IL-1 beta trigger? "Some other kind of messenger, some kind of cytokine or chemical produced by the peripheral inflammation that gets into the bloodstream and increases IL-1 beta in the central nervous system, which can then produce a very widespread induction of Cox-2," he said (see above illustration). Woolf believes that the next step, the induction of PGE2 by Cox-2, may be responsible not just for inflammatory pain but also for the more generalized symptoms—the overall aches and pains and even the loss of appetite and depression and inactivity—that accompany certain kinds of injury and inflammation. "It's such a widespread effect that it produces a change in the whole status of the nervous system, which changes our overall behavior in response to the injury," he said. "The biological imperative here is repair and healing. The way to do that is to lie in a ball somewhere quiet, don't move, slow down, let all these reparative processes occur." But if inflammatory pain is designed to slow us down so that we can heal, is there a danger in using painkillers to get rid of it? "It's an important question—why is there pain? What is it telling us? Do we need to listen to it?" Woolf said. "I think the answer is yes. But at the same time, we need to reduce suffering. Maybe the answer is, we don't need to completely eliminate pain but just reduce it to a level where it is tolerable and yet still retains some warning function." —Misia Landau |
