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ScienceWeek
NEUROBIOLOGY: ON LONG-TERM PAIN
The following points are made by Edwin W. Mccleskey (Nature 2003 424:729):
1) Normally essential to warn us of danger, pain becomes harmful when it occurs without any evident stimulus. If this persists, it can cripple a person's life. A common kind of chronic pain, called "neuropathic pain", often develops when nerves are damaged through surgery, compression by bone, diabetes, or infection. Most research on the subject parallels the study of memory, seeking to understand how the communication between neurons -- in this case, the neurons involved in transmitting pain signals -- could show long-lived enhancement. A minority view focuses on cells of the immune system and related glial cells of the nervous system, proposing that they influence the connections between nerves. That view now gains considerable support with recent evidence by Tsuda et al (Nature 2003 424:778) that spinal microglial cells use the P2X4 receptor -- a molecule with no previously known connection to the field -- to induce a form of neuropathic pain. The importance of glial biology in chronic pain now seems undeniable.
2) Pain is initiated by "nociceptive" neurons in the periphery of the body, which carry signals into the spinal cord; there, the nociceptive cells form connections (synapses) with spinal neurons. Some of these spinal neurons extend into the brain, while others form local circuits within the spinal cord. The first set of synapses in the pain pathway is considered the most significant site for "gating" pain; for example, opiates diminish the activity of such synapses, explaining much of the ability of these drugs to reduce pain. Conversely, if the synapses become hypersensitive, pain should increase. So the major goal of basic research into chronic pain is to understand how the connection between nociceptive and spinal neurons can become overly sensitized.
3) A three-step picture of the role of glia in chronic pain is now emerging. First, damage to, or inflammation of, a peripheral nerve is somehow communicated to microglia in the spinal cord. Second, these cells congregate, are activated, and respond to ATP by using newly produced P2X4 receptors. And third, the ATP-activated glial cells modify signalling between spinal neurons.
4) This picture raises many questions, and answers to any of them will suggest new ways of relieving pain. How do spinal microglia "know" that a nerve is damaged in the periphery? Where does the extracellular ATP come from? What signalling pathway within microglia is triggered by P2X4 receptors? How do the microglia communicate with and alter spinal neurons? And the two most immediate questions: is the likelihood of chronic pain lessened in humans if microglial activation is prevented following nerve damage? And is selective inhibition of P2X4 receptors a means of doing this? Some of these questions are the domain of pain neurobiologists, but others will require immunologists and glial experts to join a field that has a goal -- decreasing pain -- as old as suffering itself.
Nature http://www.nature.com/nature
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ON THE NEUROBIOLOGY OF PAIN
The following points are made by J. Yang and C. Wu (American Scientist 2001 89:126):
1) Running parallel to its long history of misconception and misinterpretation is an almost 400-year history of legitimate scientific inquiry into pain's etiology and mechanism. Such considerations began with the 17th-century philosopher, mathematician and physiologist Rene Descartes (1596-1650), who first proposed a link between peripheral sensation and the brain. While contemplating the mind-body connection, Descartes suggested that sensations stimulated in the body are conveyed directly to the brain, where they are actually perceived. Although this view is now considered overly simplistic, that should not diminish Descartes's insightful realization that sensory perception is in fact a function of the brain. The Cartesian model gave rise to the notion of a "hard-wired system", where pain signals were carried by fixed connections within the nervous system. This idea was reinforced by anatomical studies conducted during the 19th century and has endured, with a few modifications, until fairly recently.
2) In the mid-1960s R. Melzack and P. Wall (Science 1965 150:971) challenged the notion of a hard-wired system with their view that sensory information undergoes dynamic integration and modulation. The current view of nociceptive pain (pain arising from tissue damage) derives from this idea. Neuroscientists now think of the nervous system as plastic. They no longer believe the relay of pain information to be based on an immutable relationship between a painful stimulus and the sensory output of pain. Rather, the perception of pain results from the integration of information from a variety of sources. Of course information is relayed from the injured tissue or organ in the periphery, but the strength of this signal can be modified by emotional and behavioral information coming down from the brain, as well as by inputs from other peripheral sensations. Furthermore, biologists now think that the integration of these signals actually takes place in the spinal cord, not in the brain, and that the integrated information is then carried up to the brain for further processing.
3) C. Woolf and M. Salter (Science 2000 288:1765) recently enumerated the three general levels at which neural information could be modified in response to chronic pain. They noted that the extent and duration of the response to the stimulus at the periphery could be modified. Alterations can also take place at a chemical level within any one or several of the neurons along the pain-conduction pathway. These include changes in the number or sensitivity of receptors, ion channels and internal signaling molecules. Finally, chronic pain can induce a modulation of the neurotransmitters that affect the flow of information from one neuron to the next, or it can even alter the anatomical features of these neurons and their interconnections. The set of alterations described by Woolf and Salter may lead to long-term changes in the connectivity and organization among nerve cells. This, in turn, may lead to a "pain memory", not much different from ordinary memory in the brain.
American Scientist http://www.americanscientist.org
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Notes:
In mammals, including humans, the receptors for pain, called "nociceptors", are free nerve endings (i.e., endings not terminating on other neurons or muscle fibers or specialized sense receptors) found in almost every tissue of the body. These free nerve endings may respond to any type of stimulus if the stimulus is strong enough to cause tissue damage. When stimuli for other sensations, such as touch, pressure, heat, and cold, reach a certain intensity, they provoke the sensation of pain as well as the relevant primary sensation. Excessive stimulation of most sensory receptors causes pain, but pain is also caused by excessive distension or dilation of a structure, prolonged muscular contractions, muscle spasms, inadequate blood flow to an organ, or the presence of certain specific chemical substances. For example, tissue injury releases chemical entities (e.g. prostaglandins and kinins that stimulate nociceptors. In general, pain persists even after an initial tissue trauma occurs, since these substances linger and nociceptors adapt to stimuli only slightly or not at all. Because of their sensitivity to all excessive stimuli, pain receptors perform a protective function as they respond to changes that might endanger the organism.
ScienceWeek http://scienceweek.com
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