Articles: hyperalgesia.
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The clinical use of the antineoplastic agent paclitaxel (Taxol) is significantly limited in its effectiveness by a dose-related painful peripheral neuropathy. To evaluate underlying mechanisms, we developed a model of Taxol-induced painful peripheral neuropathy in the rat and determined the involvement of two second messengers that contribute to enhanced nociception in other models of inflammatory and neuropathic pain, protein kinase Cepsilon and protein kinase A. Taxol administered acutely, or chronically over 12 days, produced a decrease in mechanical nociceptive threshold. ⋯ Mechanical allodynia and thermal hyperalgesia were also present in Taxol-treated rats. Hyperalgesia, produced by both acute and chronic Taxol, was attenuated by intradermal injection of selective second messenger antagonists for protein kinase Cepsilon and protein kinase A. These findings provide insight into the mechanism of Taxol-induced painful peripheral neuropathy that may help control side effects of chemotherapy and improve its clinical efficacy.
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Selection line rats congenitally high or low for autotomy in the neuroma model of neuropathic pain (HA and LA rats) were found to be correspondingly high and low in a second type of neuropathic pain, the Chung model, which employs an alternative phenotypic endpoint, tactile allodynia. It has been proposed that both phenotypes reflect ectopic hyperexcitability in axotomized primary sensory neurons. ⋯ However, in the one neuronal subclass previously linked to neuropathic pain in these models the increase was significantly greater in HA than LA rats, and only at the time when pain scores in the two lines were diverging. Heritable differences in electrical response to axotomy in a specific afferent cell type appear to be a fundamental determinant of neuropathic pain.
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While clinical characteristics of diabetic painful neuropathy are well described, the underlying electrophysiological basis of the exaggerated painful response to stimuli, as well as the presence of spontaneous pain, are poorly understood. In order to elucidate peripheral contributions to painful diabetic neuropathy, we quantitatively evaluated the function of C-fibers in a rat model of painful diabetic neuropathy, diabetes induced by the pancreatic beta-cell toxin streptozotocin. While there was no significant effect of diabetes on conduction velocity, mechanical threshold or spontaneous activity, the number of action potentials in response to sustained threshold and suprathreshold mechanical stimuli was significantly increased in the diabetic rats. ⋯ In summary, in an established model of painful diabetic neuropathy in the rat, a subset of C-fibers demonstrated a marked hyper-responsiveness to mechanical stimuli. The subset was also found to have a greater mean conduction velocity than the fibers not demonstrating this hyper-responsivity. The present findings suggest that study of individual neurons in vitro may allow elucidation of the ionic basis of enhanced nociception in diabetic neuropathy.
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Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.
This study characterizes an animal model of persistent mechanical hyperalgesia induced by repeated intramuscular injections of low pH saline. Saline at pH 4, 5, 6, or 7.2 was injected twice, 2 to 10 days apart, into the gastrocnemius muscle of rats. To quantify hyperalgesia, paw withdrawal latency to radiant heat (heat hyperalgesia) and withdrawal threshold to mechanical stimuli (mechanical hyperalgesia) were measured. ⋯ Lidocaine injection into the gastrocnemius muscle or unilateral dorsal rhizotomy, 24 h after the second injection (pH 4), had no effect on the contralateral mechanical hyperalgesia. Minimal histopathology was observed in the injected muscle, and changes were similar between groups injected with pH 4 and pH 7.2. Thus, this new model of widespread, chronic muscle-induced pain is unrelated to tissue damage and is not maintained by continued primary afferent input from the site of injury.
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Previous studies have demonstrated that the metabotropic glutamate receptor subtype 5 (mGlu5 receptor) is expressed in the cell bodies of rat primary afferent neurones. We have further investigated the function and expression of mGlu5 receptors in primary afferent neurones, and their role in inflammatory nociception. Freund's complete adjuvant-induced inflammatory hyperalgesia of the rat hind paw was significantly reduced by intraplantar, but not by intracerebroventricular or intrathecal microinjection of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). ⋯ Immunohistochemical experiments revealed the co-expression of mGlu5 receptor protein and betaIII tubulin in skin from naive rats, indicating the constitutive expression of mGlu5 receptors on peripheral neurones. Double-labelling of adult rat DRG cells with mGlu5 receptor and vanilloid receptor subtype 1 antisera also supports the expression of mGlu5 receptors on peripheral nociceptive afferents. These results suggest that mGlu5 receptors expressed on the peripheral terminals of sensory neurones are involved in nociceptive processes and contribute to the hyperalgesia associated with inflammation.