Articles: hyperalgesia.
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Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase alpha(1) subunit but not the beta(1) subunit was expressed in rat spinal cord, particularly in the dorsal horn. ⋯ During formalin-induced long-lasting inflammation, we found that the expression of the alpha(1) subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the alpha(1) subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor-NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
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Both myelinated and unmyelinated afferents are implicated in transmitting diabetic neuropathic pain. Although unmyelinated afferents are generally considered to play a significant role in diabetic neuropathic pain, pathological changes in diabetic neuropathy occur mostly in myelinated A-fibers. In the present study, we first examined the role of capsaicin-sensitive C-fibers in the development of allodynia induced by diabetic neuropathy. ⋯ Furthermore, these afferent fibers had a lower threshold for activation and augmented responses to mechanical stimuli. Thus, our study suggests that capsaicin-sensitive C-fiber afferents are not required in the development of allodynia in this rat model of diabetes. Our electrophysiological data provide substantial new evidence that the abnormal sensory input from Adelta- and Abeta-fiber afferents may play an important role in diabetic neuropathic pain.
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Secondary hyperalgesia, an exaggerated response to stimuli applied to undamaged tissue surrounding an injury, is a common consequence of tissue injury and inflammation. It is well established that the etiology of secondary hyperalgesia is sensitization of central neurons but the exact mechanism and its role in certain clinical pain states is unclear. In the present experiments, we studied responses to punctate and non-punctate mechanical stimuli and to heat applied to the plantar aspect of the hindpaw remote to an incision in the gastrocnemius region of the rat hindlimb. ⋯ Reduced withdrawal thresholds were blocked by i.t. administration of morphine and by local anesthetic injection at the test site 2h and 2 days after gastrocnemius incision. These pharmacological data provide evidence that reduced withdrawal thresholds after gastrocnemius incision are nociceptive behaviors indicating persistent secondary hyperalgesia. Because the behaviors have a similar time course to secondary hyperalgesia in postoperative patients, the model will be useful to evaluate the mechanisms for secondary mechanical hyperalgesia after incision, its pharmacological characteristics and its potential role in persistent postoperative pain.
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The purpose of the present study was to investigate the role of mu-opioid receptor in inflammatory hyperalgesia in intact and in spinalized animals and the interaction between mu-opioid and alpha2-adrenergic receptor in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and heat stimuli were studied in mu-opioid receptor knockout mice and wildtype control mice. Thermal nociception was evaluated by measuring paw withdrawal latencies to radiant heat applied to the hindpaws. ⋯ Our observations indicate that the mu-opioid receptors do not play an important role in alpha2-adrenergic receptor agonist-mediated acute antinociception. In addition, micro-opioid receptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia, and the supraspinal control of spinal reflexes. However, in the presence of inflammation, mu-opioid receptors play an important role in the antihyperalgesic actions of an alpha2-adrenergic receptor agonist.
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J. Pharmacol. Exp. Ther. · Jan 2002
Group I metabotropic glutamate receptor antagonists block secondary thermal hyperalgesia in rats with knee joint inflammation.
Activation of ionotropic glutamate receptors has been shown previously to be essential for the development of secondary thermal hyperalgesia. The present study assessed involvement of group I metabotropic glutamate receptors (mGlu) in both the induction and maintenance phases of secondary thermal hyperalgesia initiated by knee joint inflammation in rats. The dose dependence of each drug in antagonism of thermal hypersensitivity was demonstrated in pre- and post-treatment paradigms. ⋯ Post-treatment with the group I mGlu receptor antagonists LY367385 and AIDA allowed significant recovery of the paw withdrawal latencies after the onset of the knee joint inflammation. The knee joint inflammation itself was not affected by either treatment. The results of the present study indicate that secondary thermal hyperalgesia can be effectively attenuated during both the development and maintenance phases of acute knee joint inflammation by spinal application of specific group I mGlu receptor antagonists.