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Alexandra Lopes explores the science behind feeling pain
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Have we found an on/off switch for pain in SCN9A?
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It is one thing to bear pain courageously, but remarkably, a few people do not know what pain is at all. The first scientific report of congenital indifference to pain goes back to the early twentieth century, with the description of a man who performed as a human pincushion in a circus. Since then, this condition has been well characterized. Typically, such individuals have a complete absence of any feeling of pain, in spite of having the sensation of temperature and pressure. Furthermore, they have no detectable neurological damage. The biological reason behind this condition has been unearthed only recently. In 2006, a genetic analysis was performed in three families from northern Pakistan who were indifferent to pain. The team, led by C. Geoffrey Woods, a medical geneticist at the Cambridge Institute for Medical Research, identified the gene involved—SCN9A. This gene was found to encode the alpha subunit of a voltagegated sodium channel. Sodium channels are located in the membrane of excitable
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cells, neurons in this case, and underlie the generation of action potentials by transporting sodium ions into the cell upon stimulation. In the patients who felt no pain, SCN9A was mutated, preventing proper functioning of the channel. The sodium channel encoded by SCN9A is highly expressed in neurons that transmit pain signals, and may therefore be needed to make the signals that carry information about pain to the brain. Furthermore, although it is also expressed in neurons which have functions other than pain perception, mutations in SCN9A still seem completely specific to pain. It is possible that for other stimuli, different sodium channels may compensate for SCN9A, allowing them to be felt. Indeed, although insensitive to pain, the patients studied were all able to perceive touch, temperature and pressure. This study has been extended in a recent report from researchers in Canada to a larger number of families of seven nationalities, reported to be indifferent to painful stimuli such as wounds, dental abscesses, ulcers and remarkably, to nonanesthetized surgery. According to this report, only 30 cases of this condition are known worldwide. From the two studies, it emerges that inactivating defects in SCN9A have a very similar outcome in individuals from diverse human populations. Such defects either result in a truncated form of the protein being produced, or to a process termed ‘nonsense-mediated decay’, whereby the mutation prevents the protein from being produced at all. The central role of SCN9A in pain perception mechanisms has become even
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more irrefutable by the parallel finding that other types of defects in the gene have the opposite effect, resulting in episodic acute pain syndromes. These defects seem to make the channel over-sensitive to pain stimuli.The individuals suffering from the associated disorders feel intense pain caused by everyday activities such as walking, stretching and experiencing cold. Have we found an on/off switch for pain in SCN9A? If so, this finding will have an enormous potential for the development of new analgesic drugs. Not only could the blockage of this specific sodium channel completely eliminate pain, such a drug may also avoid the sideeffects of less specific analgesics. Current neurodepressive drugs, for example the local anesthetic, lidocaine, affect all sodium channel proteins and can have dangerous effects such as cardiovascular disturbances, and can even interfere with the central nervous system when administered in high doses. As the prospect of a global analgesic rises, new concerns are thrown into the equation. By abolishing the feeling of pain, physicians will be relieving suffering, yet will also be shutting down the body’s alarm sensor. Although otherwise healthy, several patients mutant in SCN9A had accidentally harmed themselves as children due to being unable to feel pain. So whilst the discovery of SCN9A signifies promising developments in pain medicine, we should remember that pain is indeed useful, and is likely here to stay. Alexandra Lopes is a postdoc in the Department of Pathology
Sonia Aguera
Pain signifies discomfort, suffering and even agony...but not to everyone. By analysing individuals who cannot feel pain, researchers have recently found that changes to a single gene affect whether the body is capable of experiencing painful sensations. In addition to shedding light on how the body perceives pain, these findings may pave the way towards better forms of analgesic medicine. The word pain conveys a highly subjective experience with several dimensions.This includes both how pain is evaluated, for example how strong a painful sensation will feel, and also the different emotions that may be evoked from painful experiences. It is well known that pain thresholds vary between individuals. Such differences are evident in street performers who undertake daring stunts seemingly unaffected, though most other people would cry out in agony.
A schematic diagram of a voltage-gated sodium channel
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