Articles: hyperalgesia.
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Astrocytes and microglia in the spinal cord have recently been reported to contribute to the development of peripheral inflammation-induced exaggerated pain states. Both lowering of thermal pain threshold (thermal hyperalgesia) and lowering of response threshold to light tactile stimuli (mechanical allodynia) have been reported. The notion that spinal cord glia are potential mediators of such effects is based on the disruption of these exaggerated pain states by drugs thought to preferentially affect glial function. ⋯ Robust thermal hyperalgesia (tail-flick, TF, and Hargreaves tests) and mechanical allodynia (von Frey and touch-evoked agitation tests) were observed in response to i.t. gp120. Heat denaturing of the complex protein structure of gp120 blocked gp120-induced thermal hyperalgesia. Lastly, both thermal hyperalgesia and mechanical allodynia to i.t. gp120 were blocked by spinal pretreatment with drugs (fluorocitrate and CNI-1493) thought to preferentially disrupt glial function.
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We have addressed the role of the sympathetic nervous system in the development and maintenance of neuropathic pain. Using a new neuropathic mouse model, we examined the development of hyperalgesia in transgenic mice lacking functional alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if sympathetic-sensory coupling generates hyperalgesia. The development of neuropathic heat hyperalgesia required the presence of both the alpha(2A) adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the alpha(2A) adrenoceptor or the SPGN, indicating different mechanisms of sensitization. ⋯ The peripherally restricted alpha(2) antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral alpha(2) adrenoceptor plays a role in both the development and the maintenance of neuropathic heat hyperalgesia. The alpha(2) antagonist-evoked analgesia for heat stimuli was mediated by blocking peripheral and probably central alpha(2) adrenoceptors, while the analgesia for mechanical stimuli was mediated by blocking central alpha(2A) adrenoceptors. Intradermal injections with an alpha(2) agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic-sensory coupling at the level of the cutaneous nociceptor did not contribute to the maintenance of neuropathic hyperalgesia.
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An injury to a peripheral nerve in animals often leads to signs of neuropathic pain including hyperalgesia to heat, cold and mechanical stimuli. The role of injured and intact nerve fibers in mechanical hyperalgesia was evaluated in rats subjected to an L5 spinal nerve ligation-and-cut ('modified SNL lesion'). To assess the contribution of injured afferents, an L5 dorsal rhizotomy was performed immediately before, or 7 days after the modified SNL lesion. ⋯ These results suggest that, after L5 spinal nerve ligation-and-cut, mechanical hyperalgesia develops and persists independent of input from injured afferents. We propose that the Wallerian degeneration that develops after a nerve injury leads to interactions between the degenerating fibers of the injured spinal nerve and the intact fibers of adjacent spinal nerves. This leads to changes in the intact fibers that play a critical role for both initiation and maintenance of mechanical hyperalgesia.
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Musculoskeletal pain is one of the most frequent symptoms for which medical assistance is sought. Yet, the majority of our knowledge regarding pain physiology is based on studies of cutaneous tissue. Comparatively little is known about activation of visceral, joint and perhaps least of all, musculoskeletal nociceptors although clinically-treated pain originates principally in these structures. ⋯ This behavioral dependent measure is also significantly reversed by agents used clinically to treat muscle pain, indomethacin and dexamethasone, as well as the non-competitive N-methyl-D-aspartate receptor antagonist MK801. Finally, evidence that reduction in grip force is in part mediated by small, unmyelinated afferents is provided by the demonstration that neonatal capsaicin treatment significantly reduced carrageenan-evoked behavioral hyperalgesia ( approximately 45% reduction) and reduced muscle content of immunoreactive CGRP ( approximately 60% reduction) relative to control levels. Collectively, these findings provide converging lines of evidence for the validity of this animal model to investigate mechanisms involved in the development of muscle hyperalgesia.