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Unformatted text preview: Toward Better PAIN 60 SCIENTIFIC A MERIC A N C OPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. Advances in understanding the cells and molecules that transmit pain signals are providing new targets for drugs that could relieve various kinds of pain— including those poorly controlled by existing therapies CONTRO CONTROL By Allan I. Basbaum and David Julius Throbbing, itching, aching, stabbing, stinging, pounding, piercing. Pain comes in a range of unpleasant flavors. But all sentially tugged on a neural rope that then rang a pain pain has one thing in common: those who endure it alarm bell in the brain. Imagine, for example, burning a foot. “Fast moving particles of fire,” Descartes want it to stop. Yet the most widely used analgesics today are es- thought, would create a disturbance that “passes sentially folk remedies that have served for centuries: along the nerve filament until it reaches the brain.” Descartes was not too far off. Pain generally bemorphine and other opiates derive from the opium poppy, and aspirin comes from willow bark. Although gins at the periphery: in the skin, an internal organ or these treatments can give relief, each has its limita- any other site outside the central nervous system tions. Aspirin and other nonsteroidal anti-inflamma- (CNS) — that is, outside the brain and spinal cord. tory drugs (NSAIDs), such as ibuprofen, cannot ease Stubbing a toe or leaning against a hot stove activates the most severe types of discomfort. And even opiates, neurons (nerve cells) called nociceptors that respond generally the strongest medicines, do not work for ev- specifically to hurtful stimuli, such as extreme temeryone. Moreover, they can have serious side effects, perature or mechanical pressure, or to chemicals genand patients tend to become tolerant to them, requir- erated in response to injury or inflammation. ing escalating doses to get any relief at all. Nociceptors have two arms: a sensation-detecting Over the past 20 years neurobiologists have branch that projects out to the periphery, where it inlearned a great deal about the cellular circuits and the nervates small patches of tissue, and a second branch specialized molecules that carry pain signals. Today that extends into the spinal cord [see box on page 63]. this knowledge is being exploited to devise new strat- The neuron’s cell body, which resides in a structure egies for managing pain better and causing fewer side outside the spine, sits between the two. When specialeffects. Indeed, more approaches than we have room ized detector molecules on the peripheral branch ento discuss are now under study. counter a noxious agent in the skin or an organ, they trigger an impulse that travels up the line, along the central branch and on to an area of the spinal cord Particles of Fire i n t h e 17 t h c e n t u ry French philosopher René known as the dorsal horn. There the nociceptor reDescartes enumerated a theory to explain how people leases signaling molecules called neurotransmitters sense pain. In his view, a pinch, a whack or a poke es- that activate neurons in the dorsal horn, prompting SCIENTIFIC A MERIC A N w w w. s c ia m . c o m C OPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. 61 them to transmit the alarm message up it is not symptomatic of some ongoing to the brain. Although nociceptors are injury or another disease; it is itself a disoften called pain-sensing neurons, they ease of the nervous system and requires merely indicate the presence of poten- the attention of a pain specialist. tially harmful stimuli; it is the brain that interprets the signal as painful and P ain without End prompts us to say “ouch.” a m ajo r c o m m o n denominator in Not all pain is worrisome. For ex- those who suffer from hard-to-manage ample, the acute kind that accompanies pain is abnormal sensitivity to stimuli. a minor tissue injury such as a sprain or This sensitivity can take the form of hyabrasion is protective: it encourages an peralgesia (an excessive reaction to typorganism to avoid further injury. This ically painful inputs) or allodynia (pain kind tends to be temporary and to sub - in response to normally innocuous inside over time. puts). In those affected by allodynia, The pain that most troubles patients— even the gentle pressure of clothing and doctors — fails to disappear and is against one’s skin or bending a joint can difficult to treat. In many cases, the prob- become unbearable. Biologists now understand that such lem arises because the injury or the inflammation that triggers the discomfort heightened sensitivity— or sensitization— persists. The aches of arthritis result stems from molecular or structural ing. When the CNS is involved, the condition is termed central sensitization. Regardless of which specific pro cesses are at fault, ongoing pain, it turns out, can lead to sensitization and thus exacerbate and prolong discomfort. Many researchers, therefore, have amelioration of hyperalgesia and allodynia foremost in their minds as they hunt for new analgesics. Meanwhile patients need to realize that persistent pain should not be borne stoically; it requires aggressive treatment to prevent further sensitization. i n t h e s e a r c h for new analgesics, much effort has been directed toward the place where hurtful signals typically originate: the periphery. Certain of the Start at the Beginning Patients need to realize that persistent pain should not be borne stoically; it needs AGGRESSIVE TREATMENT. from ongoing inflammation, and the agony that can accompany invasive cancer stems to a large extent from tissue injury and inflammation. In other cases, persistent pain is neuropathic, resulting from damage to nerve cells themselves. It can develop when neurons in the CNS sustain damage from multiple sclerosis, a stroke or spinal cord injury, for example. Or it can derive from injury to peripheral neurons. Amputees who endure aching in a limb that is no longer there (phantom limb pain) and people who feel burning in their skin for years after a herpes infection has subsided (postherpetic neuralgia) are all suffering from neuropathic pain. When this kind of hurt continues, changes in nerve cells. In the periphery, for instance, molecules that promote inflammation may cause the nociceptors that detect noxious stimuli to become overly reactive to those inputs. Inflammatory molecules can even cause nociceptors to begin generating signals in the absence of any environmental input. Sensitization can also result from CNS changes that lead to hyperactivity of pain-transmission pathways. The changes, which may persist for a long time, can include display of increased numbers of the receptors that respond to the neurotransmitters released by nociceptors and might even include rewiring of connections and a loss of nerve cells that normally inhibit pain signalspecialized molecules that nociceptors use to detect noxious stimuli rarely occur elsewhere in the body. Blocking these molecules would presumably shut off pain signaling without disrupting other physiological processes and, thus, without causing unwanted side effects. Today’s most popular remedies — aspirin and other NSAIDs — largely work their magic in the periphery. When a tissue is injured, a variety of cells in the area pump out chemicals called prostaglandins, which act on the pain-sensing branches of nociceptors, lowering their activation threshold. Aspirin and NSAIDs inhibit the activity of a family of enzymes (cyclooxygenases) that cells use to generate the pain-inducing prostaglandins. These over-the-counter compounds relieve everyday aches and pains. But they also inhibit prostaglandin production elsewhere in the body, often causing such side effects as stomach pain, diarrhea and ulcers. These problems can prevent the drugs’ long-term use and limit the doses that can be given. To reduce the gastrointestinal consequences, pharmaceutical companies developed a family of drugs that target the JUNE 2006 Overview/Easing Pain ■ ■ Specialized nerve cells called nociceptors respond to noxious stimuli. These cells transmit a message to nerve cells in the spinal cord, which then carry the signal to the brain. Nociceptors and other nerve cells in pain circuits possess specialized molecules for detecting pain-causing stimuli. These molecules can serve as targets for the development of medicines that may alleviate pain with fewer side effects than are caused by existing drugs. 62 SCIENTIFIC A MERIC A N J A N A BR E NNING ( pr eceding pages) FEELING THE PAIN The pain circuit, shown here in simplified form, extends from the body’s periphery — the skin and other tissues outside the central nervous system — to the spinal cord and brain. Hurtful stimuli activate special pain-sensing nerve cells, or nociceptors ( pink), which generate impulses that convey word of the trouble to nerve cells in the dorsal horn region of the spinal cord (blue). Those cells, in turn, pass the message to the brain, which interprets it as pain. Impulse (pain message) Intestine Peripheral branches of nociceptors Dorsal root ganglion “Pain” Projection to brain being prescribed to relieve the itching, prickling and stinging sensations that can accompany postoperative wound healing or nerve impairments stemming from HIV infection, bouts of herpes and diabetes. Exactly how the ointments work is unclear, although small doses over time might ultimately make the receptor less responsive to the usual stimuli or might cause depletion of the neurotransmitters emitted by nociceptors. Inflammation Dorsal horn of spinal cord Cell body of nociceptor Tissue injury Dorsal horn nerve cell enzyme cyclooxygenase-2 (COX-2). Because COX-2 does not normally operate in the stomach or intestinal tract, blocking its activity should not cause the same disruptions as traditional NSAIDs do. Whether they are in fact gentler on the stomach remains to be established. In the meantime, the drugs have problems of their own. Rofecoxib (Vioxx), a COX-2 inhibitor that had been prescribed for relief of arthritis pain, was removed from the market when it was found to boost the risk of heart attack and stroke. Other COX-2 inhibitors are also being scrutinized for ill effects. disc ov e ry of ta rg e t s that reside almost exclusively on nociceptors provided an opportunity to develop drugs that act selectively to relieve pain. A particularly appealing one is the capsaicin receptor. This ion channel, present in the membrane of many nociceptors, responds not only to capsaicin, the pungent ingredient in chili peppers, but also w w w. s c ia m . c o m S end in the Salsa to distressful heat and to protons (the hydrogen ions that make substances acidic); protons are unusually abundant in inflamed tissue. In the presence of these chemicals or of temperatures above 43 degrees Celsius, the channel allows sodium and calcium ions to flood into the nociceptor, stimulating it to generate a signal that translates into the burning sensation induced by heat, inflammation or spicy food. Substances that inhibit the capsaicin receptors should therefore dampen inflammatory pain. Indeed, in laboratory animals, such “antagonists” have been able to relieve the very severe pain caused by the acidic environment around tumors that have metastasized to and damaged bone tissue. Today many pharmaceutical companies are competing to develop capsaicin receptor antagonists. The possibilities for manipulating the receptor do not end there. Ironically, in some instances, purposely stimulating capsaicin receptors can alleviate pain. Topical creams containing capsaicin are a d i f f e r e n t k i n d of molecule found on the peripheral terminals of nociceptors is also attracting interest as a drug target. All neurons possess sodium channels that open in response to changes in the voltage across the nerve cell membrane, generating the impulses that relay messages from one neuron to the next. Local anesthetics that temporarily inactivate such voltage-gated sodium channels currently treat a variety of different pains, particularly those arising from a trip to the dentist. The problem, though, is that those anesthetics have to be applied at the site of the discomfort: disabling sodium channels throughout the nervous system could be fatal. Pain-sensing neurons, however, possess a subclass of voltage-gated sodium channels, known as the TTX-resistant type, that do not occur in the CNS. Investigators therefore hope that drugs able to block this subclass could be administered systemically (throughout the body) without ill effects. Moreover, studies suggest that such agents could well dampen inappropriate hyperactivity by injured peripheral nerves and thus might relieve some neuropathic pain. Unfortunately, the pharmaceutical industry has so far been unable to successfully develop selective inhibitors for such channels, in part because they closely resemble TTX-sensitive sodium channels, which appear widely throughout the nervous system. The channels could perhaps be selectively removed, however, with a new technique called RNA interference. The method relies on introducing into an organism tiny molecules known as small interfering RNAs (siRNAs). These SCIENTIFIC A MERIC A N Block Other Channels AMADEO BACHAR C OPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. 63 DRUG TARGETS IN THE PERIPHERY The small branches of nociceptors that innervate the skin and internal organs possess specialized molecules — receptors — that detect noxious stimuli. Those stimuli can include the chemical capsaicin in hot peppers, intense heat or substances released by the inflammatory cells that respond to an injury. Recognition by the detectors causes some of them to usher sodium and calcium ions into the cells. This inflow or the activaSkin Area of detail Peripheral branch of nociceptor tion of other receptors induces nociceptors to emit pain signals and can make the cells responsive to innocuous stimuli. Signal propagation also requires activation by voltage-gated ion channels. Inhibiting the activity of the detector molecules or of the voltage-gated channels should be therapeutic, in the ways indicated in the boxes. For clarity, only some of the drug targets being explored are noted. Targets: Capsaicin receptor and ASIC Inhibitors should reduce the pain accompanying inflammation. Capsaicin Capsaicin receptor Calcium ion Target: TTX-resistant sodium channels Blockers would silence signaling by nociceptors and should not interfere with signaling by other nerve cells. TTX-resistant voltage-gated sodium channel Burning heat Proton COX enzyme Sodium ion ASIC (acid-sensing ion channel) Bradykinin receptor Target: Bradykinin receptor Inhibitors could ease pain related to inflammation. Skin Tissue damage Bradykinin Prostaglandin Inflammatory cell Prostaglandin receptor Target: Prostaglandinproducing enzymes Nociceptor terminal Aspirin, ibuprofen and COX-2 inhibitors reduce production of prostaglandins by inflammatory cells. Blockers that might have fewer side effects are under study. siRNAs prevent the production of an unwanted protein by inducing the degradation of the molecules (messenger RNAs) that direct the protein’s synthesis. The technique is being studied in humans for certain retinal conditions, but turning RNA interference into a pharmacological intervention for pain will be challenging. As is true of gene therapy, a virus will most likely be needed to deliver siRNA, and this aspect has raised safety concerns. Time will tell whether the approach will be practical as a pain therapy, but it remains an exciting possibility. Suppose drug companies do develop nist that blocks its receptors would cera so-called magic bullet analgesic: a tainly prevent those receptors from acticompound that specifically and effec- vating nociceptors. But it would not stop tively eliminates the activity of one of the neurons from recognizing and rethe pain-transducing molecules on noci- sponding to other pain-inducing moleceptors. Would this intervention provide cules generated by injury or inflammarelief from intractable pain? Maybe not, tion — protons, prostaglandins, and a because closing off a single entrance to protein called nerve growth factor, for the pain pathway might not be enough. example. Similarly, hobbling only the Imagine, for example, a pharmaceu- capsaicin receptors might not mitigate tical that knocks out the receptor for all proton-mediated pain, because under bradykinin— a small protein, or peptide, certain circumstances, protons activate that is produced during inflammation in a separate population of detectors, called the periphery. Bradykinin powerfully ASICs (acid-sensing ion channels), on stimulates nociceptors, and an antago- nociceptors. JUNE 2006 64 SCIENTIFIC A MERIC A N COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. AMADEO BACHAR o n e way a rou n d this redundancy problem would be to administer a cocktail of inhibitory molecules that targets multiple pain mechanisms. Another approach, though, would target molecules that act more centrally, blocking the ability of all nociceptors — no matter what stimuli initially activated them— to pass their pain signals to spinal cord neurons. Morphine and other opiates, which bind to opioid receptors on the nociceptor endings that reach into the spinal cord, employ this latter tactic. In activating these receptors, opiates prevent neurotransmitter release, thus blocking the transmission of the pain message to spinal cord neurons. They also render dorsal horn neurons less able to respond to pain signals. Because these drugs act in Focus on the Cord neurotransmitters from nociceptor end- carrier of the pain message. Glutamate ings in the spinal cord. Gabapentin (Neu- activates various receptors in the dorsal rontin), an anticonvulsant, is believed to horn of the spinal cord. Of these, the relieve some forms of pain by interacting NMDA class participates in central senwith a specific subunit of certain calcium sitization, which makes it a logical tarchannels. And a relatively new drug get for new analgesics. called ziconotide (Prialt) — derived from Every neuron in the body possesses the venom of a Pacific Ocean cone snail— some type of NMDA receptor. Conse inhibits a different variety of calcium quently, inhibiting all types at once would elicit catastrophic effects, includchannel known as the N-type. Like opioid receptors, N-type calci- ing memory loss, seizures and paralysis. um channels occur throughout the ner- To avoid such reactions, researchers are vous system. If ziconotide were delivered attempting to hobble the receptor by systemically, blood pressure would de - acting on versions found mostly in the cline precipitously. So the compound is dorsal horn. Compounds that bind to a administered intrathecally. Although the form containing what is called the toxin blocks pain, its action within the NR2B subunit have yielded encouragCNS can still generate unpleasant side ing results in animal studies. For exameffects, including dizziness, nausea, ple, mice that had an NR2B inhibitor headache and confusion. Ziconotide, delivered directly into the spinal fluid Investigators might be able to develop better COGNITIVE THERAPIES for altering pain perception. the spinal cord, they should in theory be therefore, is given mostly to patients with were less sensitive to pain than were unable to treat all types of pain, although late-stage cancer who cannot get relief treated animals. The drug also reversed they tend to work best against those re- another way [see “A Toxin against Pain,” allodynia in mice that had a peripheral by Gary Stix; Scientific American, nerve injury. lated to inflammation. A number of nociceptors also release Unfortunately, opioid receptors are April 2005]. Recently drugs that act on cannabi- peptide neurotransmitters, such as subpresent on neurons throughout the body, including in the brain and the gastroin- noid receptors — the ones that mediate stance P and calcitonin gene–related testinal system. This ubiquity explains marijuana’s effects — have been advanc- peptide (CGRP). These peptides actiwhy morphine and its cousins can gen- ing through clinical trials. These agents vate pain-transmission neurons in the erate a broad set of undesirable side ef- seem to ease pain in several ways, includ- spinal cord by acting on discrete recepfects, including severe constipation and ing by interfering with signal transmis- tors, so drugs that bar interaction with respiratory shutdown. These problems sion between nociceptors and their tar- those receptors would be expected to be can restrict the amount of drug a patient get cells and by reducing the activity of helpful. Regrettably, selective blockade can take safely or that a doctor will pre- inflammatory cells. of the receptor used by substance P— the scribe. And many physicians are relucneurokinin-1, or NK-1, receptor— has tant to prescribe opiates for fear patients Batten Down the Hatches failed in clinical trials for pain, perhaps will become addicted. Addiction, how- s o m e i n v e s t i g a t o r s are concen- because blocking that receptor by itself ever, is not common in those who take trating on preventing spinal neurons is insufficient. Whether quieting CGRP opiates only for pain. In part to avoid from responding to neurotransmitters activity in the spinal cord will shut down some of the undesirable effects, opiates released by nociceptors — particularly to pain is unknown, although the pharmaare often delivered directly into the fluid- the amino acid glutamate, the primary ceutical industry is developing antago filled space around the spinal cord (intrathecally). The medicines may also be ALLAN I. BASBAUM and D AVID JULIUS often collaborate on studying the cellular and mo administered by injection (for postop lecular mechanisms that underlie pain. Basbaum, who received his Ph.D. in neuroscience erative pain) or via an indwelling pump from the University of Pennsylvania, is professor and chair of the department of anatomy (for chronic pain). at the University of California, San Francisco. Julius, who received his Ph.D. in biochemistry Alternatives to opiates are available from U.C., Berkeley, is professor of cellular and molecular pharmacology at U.C.S.F. Both as well. Medicines that interfere with calauthors consult for companies pursuing therapies for pain— among them GlaxoSmithKline, cium channels can prevent the release of Hydra Biosciences, NeurogesX and Rinat Neuroscience. THE AUTHORS w w w. s c ia m . c o m C OPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. SCIENTIFIC A MERIC A N 65 nists that aim to ease the agony of migraines by interfering with the release of CGRP onto blood vessels on the surface of the brain. i f a l l at t e m p t s to modulate pain signaling fail, one can consider killing the messenger. Cutting nociceptive nerves, though, generally backfi res because, as we have noted, nerve injury can promote the onset of even more stubborn, persistent pain. Severing pathways in the spinal cord that convey information to the brain (cordotomy) was once common but now is reserved for terminal cancer patients unresponsive to all pain treatments. The problem with this last procedure is that the surgeon cannot selectively cut the “pain” pathways. A possible solution, now drawing K ill the Messenger? considerable attention because of its suc- that trim back the signal-detecting cess in animals, is a molecular therapy branches of nociceptors — such as high that takes out a subset of the spinal cord doses of capsaicin— would halt pain but neurons receiving input from nocicep- allow the branches to grow back eventutors. This cell-killing therapy couples ally, restoring normal pain detection to saporin, a toxin, to substance P. The sub- the patch of tissue innervated before. stance P in the conjugate binds to NK-1 Targeting neurons may not be the receptors, leading to internalization of sole way to overcome pain. Studies indithe whole compound, after which the cate that glia, the cells that nurture neusaporin is freed to kill the neuron. Be- rons in the CNS, swing into action in cause the conjugate can enter only cells response to damage to peripheral nerves. having an NK-1 receptor, researchers The glia migrate to the region of the dorhope that side effects will be limited. sal horn associated with the injured Ablation of neurons in the spinal cord, nerves. Then the glia discharge a bevy of however, should be considered a method chemicals that prod nociceptor terminals of last resort: neurons in the CNS do not to release neurotransmitters in the cord, grow back, so the resulting changes— for thus perpetuating a pain signal. Some of better or worse— will be permanent. The these substances, including growth facsame permanence does not hold in the tors and molecules known as cytokines, peripheral nervous system, where cut fi- also make dorsal horn neurons overly exbers can regenerate. Ideally, therapies citable, and drugs blocking that hyperac- DRUG TARGETS IN THE SPINAL CORD For pain signals from nociceptors to get relayed to the brain by nerve cells in the spinal cord, the nociceptors must release chemical signals, such as glutamate and substance P, into the dorsal horn of the cord. These chemicals must then be detected by specific receptors on dorsal horn nerve cells. What is more, for nociceptors to release their signaling molecules, calcium channels on nociceptor terminals must open. Morphine and related opiates, currently among the most effective painkillers, work in part by activating opioid receptors that inhibit calcium channels. But opiates can have unacceptable side effects, so agents are being sought that act on other targets in the spinal cord. Nociceptor Dorsal horn nerve cell Pain signal Nociceptor terminal in spinal cord Glutamate Calcium ions Calcium channel Sodium ion Calcium ion Pain-transmitting dorsal horn nerve cell Target: NMDA receptors Target: Calcium channels on nociceptors Some existing drugs, such as gabapentin (Neurontin) and ziconotide (Prialt), ease pain by inhibiting specific calcium channels on nociceptors; other blockers are being considered. Substance P NK-1 receptor Inhibitors could impede transmission of pain signals by dorsal horn nerve cells and combat hypersensitivity of those cells. NMDA receptor Target: NK-1 receptors AMADEO BACHAR Opioid receptor Researchers hope that substance P can be used to ferry a toxin into dorsal horn cells bearing NK-1 receptors, thus killing the cells and halting their pain signaling. 66 SCIENTIFIC A MERIC A N COPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. JUNE 2006 PAIN FIGHTERS IN DEVELOPMENT The table below highlights some compounds with novel mechanisms of action that are being tested in people; it thus omits new variants of well-established pharmaceutical classes, such as opiates and COX inhibitors. Clinical trials advance in stages, with phase I focusing on safety, phase II consisting of early trials of efficacy and phase III involving much larger tests. COMPOUND (DEVELOPER) MECHANISM OF ACTION TRIAL STAGE COMPANIES STUDYING RELATED AGENT AMG-517 (Amgen) EVT-101 (Evotec) Icatibant (Sanofi-Aventis) NGX-4010 (NeurogesX) NMED-160 (Neuromed Pharmaceuticals) Ralfinamide (Newron Pharmaceuticals) RN624 (Rinat Neuroscience) SAB-378 (Novartis) Blocks the capsaicin receptor Blocks NMDA receptors bearing the NR2B subunit Blocks a bradykinin receptor Overstimulates the capsaicin receptor Blocks N-type calcium channels Blocks sodium channels Stops nerve growth factor from s timulating nociceptors Activates a cannabinoid receptor Phase I Phase I Phase II Phase III Phase II Phase II Phase II Phase II Amgen GW Pharmaceuticals; GlaxoSmithKline GlaxoSmithKline; Neurogen Roche; Merck & Co. Merck & Co. S O U R C E : F R A N Z F. H E F T I R i n a t N e u r o s c i e n c e C o r p o r a t i o n tivity should help undercut excessive sensitivity. Various groups are working to identify— and find ways to inhibit— the molecules that recruit and activate glia when nerves are damaged. Interestingly, prostaglandins are among the key substances released from activated glia in the spinal cord. There they enhance pain by blocking receptors for glycine on dorsal horn neurons. Glycine, an inhibitory neurotransmitter, normally quiets these neurons. NSAIDs may therefore work not only by interfering with the production of prostaglandins in the periphery (the familiar way) but also by inhibiting COX enzymes in glia. In that case, direct delivery of COX inhibitors into the spinal fluid might minimize the side effects caused by systemic delivery. A pharmaceutical that enhanced glycine receptor activity could also help tamp the transmission of pain messages to the brain. i n t h is a rt icl e we have discussed a subset of the experimental approaches to treating pain, all of which have shown promise in animal studies. Those evoking the greatest excitement leave normal sensation intact while diminishing the heightened sensitization characteristic of the difficult-to-treat inflammatory and neuropathic pains and have an acceptable side-effects profile. But will these w w w. s c ia m . c o m A Question of Perception therapies help patients? And will they work on all types of pain? These questions remain unanswered. One approach that deserves further exploration is the use of behavioral, nondrug therapies for intractable pain— particularly that associated with conditions such as fibromyalgia and irritable bowel syndrome, for which no one has conclusively established an organic cause. Roughly a decade ago researchers at McGill University demonstrated that hypnosis could alter brain activity along with a person’s perception of pain. The scientists hypnotized volunteers and suggested to them that the hot water bath in which they had immersed their hands was either more unpleasant or less unpleasant than it really was. Using positron-emission tomo graphic scanning to monitor brain activity, the investigators found that the somatosensory cortex, which responds to the magnitude of the physical stimu- lus, was equally active in both situations. But a second brain region, the cingulate cortex, was more active when subjects believed that the stimulus was more unpleasant, suggesting that hyp nosis changed the way these individuals perceived sensations. By learning more about how the brain modulates the pain experience, investigators might be able to develop better cognitive therapies for moderating pain perception. Poet Emily Dickinson often contemplated pain. In one work, she noted: Pain has an element of blank; It cannot recollect W hen it began, or if there were A day when it was not. It has no future but itself. We can only hope continued research into the mechanisms of pain sensation will lead to safe, effective treatments that will alter pain’s future, such that it reverts to a time when it was not. MORE TO EXPLORE The Perception of Pain. A . I. Basbaum and T. Jessel in Principles of Neural Science. Edited by Eric R . Kandel et al . McGraw-Hill, 2000. M olecular Mechanisms of Nociception. David Julius and Allan I. Basbaum in Nature, Vol. 413, pages 203–210; September 13, 2001. Immune and Glial Cell Factors as Pain Mediators and Modulators. S . B. McMahon, W. B. Cafferty and F. Marchand in Experimental Neurology, Vol. 192, No. 2, pages 444–462; 2005. P ain Collection in Nature Reviews Neuroscience, July 2005. Available online at w ww.nature.com/nrn/focus/pai n Emerging Strategies for the Treatment of Neuropathic Pain. Edited by James N. Campbell et al. IASP Press, 2006. SCIENTIFIC A MERIC A N C OPYRIGHT 2006 SCIENTIFIC AMERICAN, INC. 67 ...
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This note was uploaded on 10/14/2010 for the course ZOO 4125 taught by Professor Flanigan during the Fall '10 term at Univeristy of Wyoming- Laramie.

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