Articles: hyperalgesia.
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Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5-hydroxytryptamine (5-HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5-HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). ⋯ The tissue concentration of 5-HT was measured using microdialysis. Concentrations of 5-HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5-HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2A receptors.
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The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. ⋯ Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C epsilon, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.
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Glial activation is known to contribute to pain hypersensitivity following spinal sensory nerve injury. In this study, we investigated mechanisms by which glial cell activation in medullary dorsal horn (MDH) would contribute to tactile hypersensitivity following inferior alveolar nerve and mental nerve transection (IAMNT). Activation of microglia and astrocytes was monitored at 2 h, 1, 3, 7, 14, 28, and 60 days using immunohistochemical analysis with OX-42 and GFAP antibodies, respectively. ⋯ There was no significant loss of trigeminal ganglion neurons by 28 days following IAMNT, suggesting that degenerative changes in central terminals of primary afferents might not contribute to glial activation. Minocycline, an inhibitor of microglial activation, reduced microglial activation, inhibited p38 mitogen-activated protein kinase (MAPK) activation in microglia, and significantly attenuated the development of pain hypersensitivity in this model. These results suggest that glial activation in MDH plays an important role in the development of neuropathic pain and activation of p38 MAPK in hyperactive microglia contributes to pain hypersensitivity in IAMNT model.
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Br J Clin Pharmacol · Apr 2006
Randomized Controlled TrialHyperalgesia induced by cutaneous freeze injury for testing analgesics in healthy volunteers.
The early phases of the clinical development of new analgesic agents are severely hindered by a lack of reliable sensitive tests based on experimental pain models. The aim of this study was to assess the ability of a localized hyperalgesia model induced by cutaneous freeze injury to evaluate the pharmacodynamic profile of weak analgesic agents in healthy volunteers. ⋯ Cutaneous freeze injury coupled with a von Frey electronic device to assess the mechanical pain threshold is a convenient model that causes no discomfort. The improved sensitivity and stability of this experimental model of hyperalgesia over three consecutive days make it a useful tool for evaluating the efficacy and detecting the potential sites of action of analgesic agents such as nonsteroidal anti-inflammatory drugs in healthy human subjects.