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Neuralgia - what is it? Neuralgia = pain at the nerve endings, usually induced by a disturbed "food" supply of a nerve
Chronic Pain PathwaysChronic pain is not just a prolonged version of acute pain. As pain signals are repeatedly generated, neural pathways undergo physiochemical changes that make them hypersensitive to the pain signals and resistant to antinociceptive input. In a very real sense, the signals can become embedded in the spinal cord, like a painful memory. The analogy to memory is especially fitting since the generation of hypersensitivity in the spinal cord and memory in the brain may share common chemical pathways. Activation of NMDA Receptors. The main neurotransmitter used by nociceptors synapsing with the dorsal horn of the spinal cord is glutamate, a versatile molecule that can bind to several different classes of receptors. Those most involved in the sensation of acute pain, AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic-acid) receptors, are always exposed on afferent nerve terminals. In contrast, those most involved in the sensation of chronic pain, NMDA (N-methyl-D-aspartate) receptors, are not functional unless there has been a persistent or large-scale release of glutamate. Repeated activation of AMPA receptors dislodges magnesium ions that act like stoppers in transmembrane sodium and calcium channels of the NMDA receptor complex. The conformational change in the neuronal membrane that makes these receptors susceptible to stimulation is the first step in central hypersensitization (Figure 3) and marks the transition from acute to chronic pain.
Activation of NMDA receptors has a number of important consequences (Table 1). Because activation causes spinal neurons carrying pain to be stimulated with less peripheral input (a phenomenon known as windup), less glutamate is required to transmit the pain signal, and more antinociceptive input is required to stop it. Endorphins and other naturally occurring pain-relievers cannot keep up with the demand and essentially lose their effectiveness. So do opioid medications at the usually prescribed dosage. The clinical implications are clear but underappreciated--inadequately treated pain is a much more important cause of opioid tolerance than use of opioids themselves.
Activation of NMDA receptors can also cause neural cells to sprout new connective endings. This neural remodeling can add new dimensions to old sensations. The emotional component of pain may be increased, for example, if the new connections channel more of the pain signal to the reticular activating system of the brain. When that occurs, the signal's pathway into the cerebral cortex is more splayed and the pain signal more diffuse and difficult to localize. Neural remodeling may also precipitate the destruction and loss of cells. Some of the brain damage that occurs during strokes is believed to be caused by the torrents of glutamate released from injured presynaptic cells, which overstimulate NMDA receptors on adjacent postsynaptic cells and effectively burn them out. The same phenomenon may occur in parts of the spinal cord receiving persistent pain signals. There is also evidence that NMDA receptor activation can stimulate normal apoptotic mechanisms. Although some of the details have yet to be elucidated, the data obtained thus far suggest that chronic pain is a destructive process that requires timely treatment in order to limit the damage that it causes. Activation of NK-I Receptors. A further effect of NMDA-receptor activation is that it causes nociceptors to release the peptide neurotransmitter substance P, which binds to neurokinin-1 (NK-1) receptors in the spinal cord. Activation of these particular receptors amplifies the pain signal and also stimulates nerve growth and regeneration. It is thus interesting to note that the one chemical abnormality repeatedly documented in controlled studies of patients with fibromyalgia syndrome is an elevated level of substance P in the spinal fluid. In animal models of chronic pain, substance P binding to NK-1 receptors induces production of the c-fos oncogene protein, which in many respects can be regarded as a biochemical footprint of chronic pain. The presence of c-fos protein in spinal cord cells is a marker for central hypersensitization. At first, it is detectable in afferent spinal cord cells actively receiving pain signals. With persistence of the pain, the protein spreads to progressively higher levels of the spinal cord until it eventually reaches the thalamus, at which point the pain is virtually untreatable. This model explains why patients who have had uncontrolled pain for months or years often find that their pain has spread beyond the originally affected organ or dermatome. In these cases, physicians who are not familiar with the concept of neural plasticity are apt to conclude that the pain is psychogenic, because it does not conform to their preconceived map of the nervous system. Afferent Becomes Efferent. Although most of us were taught that neuronal cells transmit signals in only one direction, either towards (afferent) or away (efferent) from the brain, we now know that many neurons can carry signals in both directions. With the prolonged generation of pain signals, a dorsal root reflex can become established. This is a pathologic condition in which afferent cells in the dorsal horn release mediators that cause action potentials to fire antidromically (i.e., backwards down the nociceptors). When this happens, packets of chemicals located at the peripheral terminals of these cells are released. Among these chemicals are nerve growth factor and substance P, which is not only a neurotransmitter but also a potent inflammatory agent. Nerve growth factor increases the excitability of nociceptors. Pain signals from peripheral nerves are thus heightened, and the cycle of chronic pain is continued (Figure 4).
Neurogenic Inflammation. The release of substance P and nerve growth factor into the periphery causes a tissue reaction termed neurogenic inflammation. In contrast to the classic inflammatory response to tissue trauma or immune-mediated cell damage, neurogenic inflammation is driven by events in the central nervous system and does not depend on granulocytes or lymphocytes. Substance P causes degranulation of mast cells, and its effects on the vascular endothelium induce the release of bradykinin and production of nitric oxide, a potent vasodilator. Biopsy specimens from neurogenically inflamed tissues--e.g., tendon insertion sites in fibromyalgia, the synovium in certain forms of chronic arthritis, the bladder in interstitial cystitis, or the colon in severe irritable bowel syndrome--typically show vasodilatation, plasma extravasation, abnormal sprouting of peripheral nerve terminals, and an accumulation of mast cells. Hyperalgesia and Allodynia. Chemosensitive afferent nerves may become so sensitized by persistent pain that a low-intensity stimulus will provoke hyperalgesia. In certain syndromes, the pain signals may also activate the usually quiet mechanosensitive afferent nerves that are present in synovial tissue and all viscus organs. Once activated, even slight movement or minimal deformity of surrounding tissues can generate pain. This phenomenon, allodynia, is common in chronic degenerative arthritis, low back pain, and severe irritable bowel syndrome and interstitial cystitis. Text made available by Daniel Brookoff, M.D., University of Tennessee
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