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NEUROLOGY

Adjusting the theory of pain

Adaptations of traditional approaches lead to new insights into phantom pain and other phenomena

052-053_Dor_239The pain that is felt in a phantom limb—in a part of the body that no longer exists, for instance—is no fantasy brought about by the loss of an arm or a leg.  The pain might be indeed real.  One of the hypotheses that have been raised to explain this phenomenon suggests that the regrowth of nerve fibers around the absent body part produces involuntary stimuli that the brain interprets as pain.  Another hypothesis, introduced recently, suggests that when nerve fibers transmitting stimuli to the medulla are ruptured, medullar   neurons can become hypersensitive and carry pain signals to the brain, even when stimuli that normally elicit sensations of pain are absent.

Basing his view on a proposal for readjusting the classic, 50-year-old theory of pain physiology, Francisco Javier Ropero Peláez, a professor at the Federal University of the ABC in Santo André, thinks more along the lines of this second hypothesis.  Paláez’s approach also offers new insights into dysesthesia, a neurological disturbance that can cause a mere touch to be interpreted as a stimulus capable of triggering intense pain (such as fibromyalgia, accompanied by chronic, generalized muscle pain).

In a 1965 article in Science, psychologist Ronald Melzak of McGill University and MIT neuroscientist Patrick Wall introduced their “gate control” theory of pain, building on existing approaches and careful analysis of René Descartes’s 1664 treatise on the subject.  Often mentioned in the neurological literature, the Melzak/Wall approach describes how neurons interpret different stimuli that the brain might or might not perceive as pain.  According to their theory, there are two kinds of stimuli: the first travels from nociceptive cells, in the form of thin nerve fibers, innervating skin, muscles, bones, and internal organs, triggering aversive signals such as those of intense heat (fire) or a deep cut, as from a knife (see Pesquisa FAPESP Issue nº 155); and the second stimulus, originating from the endings of large nerve fibers, is triggered mechanically through touch, pressure, or vibration.

The two types of fibers conduct signals to two types of medullar neurons that act as gateways for pain transmission, either blocking or releasing stimuli.  When receiving stimuli from both types of fibers, the first neuron (interneuron) transmits the signal to the second neuron only if the stimulus originates from the nociceptive fiber.  This theory explains how people are able to use electric hair-removal devices, which work by massaging the skin, relieving the sensation of pain even as the follicles are being pulled out.

Hypotheses
In 2014, Lorne Mendell of the University of New York at Stoney Brook remarked that the model that Melzak/Wall presented in their Science article “is incorrect in every detail.”  One year earlier, two Canadian researchers pointed out an excessive number oversimplifications and errors in the Melzak/Wall theory’s presentation of both the neural architecture of the spinal cord and the location and interaction of nerve fibers.  Peláez was particularly unsettled by the claim that the nociceptive fiber can at once inhibit one neuron and stimulate another.  In his view, inhibition cannot occur because the substances responsible for transmitting or blocking stimuli (identified sometime after the publication of the 1965 Science article) cannot trigger contrary responses from the endings of a single neuron.

The discovery of this likely error, along with evidence pointing to the adaptability of neurons, encouraged Peláez and Professor Shirley Taniguchi, a pharmacologist at the Albert Einstein College of Health Sciences, to create a neuro-computational model (described in the journal Neural Plasticity, November, 2015) that allows for variations in neural sensitivity and interconnectedness in the face of stimuli.  In 1996, researchers at the University of Bath in the UK, having devised a mathematical model to explain certain phenomena in connection with pain, had already observed variations in the sensitivity of neurons responding disproportionately to changes in the intensity of stimuli.

According to Peláez, pain triggered by tactile stimuli—such as that found in certain varieties of dysesthesia—can occur when nerve fibers transmitting mechanical stimuli lose a layer of their lining and, consequently, interpret signals more slowly (similar to aversive-stimuli fibers), thereby confusing the medullary neurons as to the signal’s origin.  “There are several other hypotheses for explaining hypersensitivity to pain,” says Thiago Cunha, a professor and pharmacologist at the Ribeirão Preto School of Medicine (FMRP-USP).  According to Cunha, there is evidence suggesting that interneurons can lose their capacity for target selectivity—or even die—allowing signals to travel more easily through pathways to the brain.  Another hypothesis raises the possibility of a reduction in the function or levels of the GABA neurotransmitter (which inhibits nerve stimuli), or that GABA-receptors malfunction and stimulate the neurons that they would normally inhibit.

After developing and publishing his own pain gate theories, Peláez went on to discuss his approach with biomedical researchers, respond to the bewilderment that arose over his mathematical interpretation of biological phenomena, and, finally, demonstrate how his work could be useful.  According to Taniguchi, with whom he co-wrote his Neural Plasticity article, Peláez’s new approach explains how drugs like gabapentin (which inhibits neural sensation) work.  According to their theory, Taniguchi and Peláez suggest that phantom pain can be controlled by administering gabapentin immediately following amputation and before medullar neurons become hypersensitive and release pain signals despite the absence of actual stimuli.

Scientific articles
MELZACK, R. and WALL, P. D. Pain mechanisms: a new theoryScience.  V. 150, no. 3699.  1965.
MOAYEDI, M. and DAVIS, K. D. Theories of pain: from specificity to gate controlJournal of Neurophysiology.  V. 109, no.  2013.
PELÁEZ, F.  J. R. and TANIGUCHI, S.  The Gate Theory of pain revisited: Modeling different pain conditions with a parsimonious neurocomputational modelNeural Plasticity.  V. 752807.  2015.
MENDELL, L. M. Constructing and deconstructing the gate theory of painPain.  V. 155, no. 2.  2014.

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