Articles: hyperalgesia.
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Since evidence points to the involvement of cholecystokinin (CCK) in nociception, we examined the effect of intrathecal CI-988, an antagonist of the CCK-B receptors, on mechanical hyperalgesia and allodynia in normal, mononeuropathic and diabetic rats,. Owing to the anti-opioid activity of CCK, it has been suggested that hyperactivity in the spinal CCK system is responsible for the low sensitivity of neuropathic pain to opioids. We therefore also evaluated the effect of the combination of i.t. ⋯ The combination of CI-988 and morphine showed a superadditive interaction in the diabetic rats only (477 +/- 16 g; cut-off 750 g), in comparison with the antinociceptive effect of each drug. In addition, CI-988 exhibited a weak anti-allodynic effect in mononeuropathic rats, and no anti-allodynic effect in diabetic rats. These results show the CCK-B receptor blockade-mediated antinociceptive effects and reveals the antinociceptive action of morphine in diabetic rats after CCKergic system inhibition.
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J. Pharmacol. Exp. Ther. · Oct 2000
Antinociceptive effect of pregabalin in septic shock-induced rectal hypersensitivity in rats.
Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interaction with the alpha(2)delta-subunit of voltage-dependent Ca(2+) channels. In this study, we investigate the antinociceptive activity of pregabalin in a rat model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharide (LPS) administration. LPS (Escherichia coli, serotype O111:B4) leads to a delayed lowering threshold (9-12 h) of abdominal contractions in response to rectal distension (RD) in awake rats surgically prepared for electromyography of abdominal muscles. ⋯ When administered 2 h before RD (but preceded 12 h by LPS injection), the oral dose of 10 mg/kg was effective both in the allodynic response induced by LPS and in the intensity of the nociceptive response related to RD. Pretreatment by either naloxone or bicuculline (a GABA(A) antagonist, 0.5 mg/kg i.p.) did not affect the antiallodynic effect of pregabalin. We conclude that pregabalin is a therapeutic candidate in the treatment of gut hypersensitivity not acting through GABA(A) and opiate receptors.
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Substance P (SP) is an important neuromediator in the spinal processing of nociceptive afferent information. Our previous study has shown that spinal (intrathecal, IT) application of SP produces thermal hyperalgesia that is mediated by activation of the G-protein coupled NK1 receptor. The activation of some classes of the G-protein coupled receptors is known to produce diacylglycerol with consequent activation of protein kinase C (PKC). ⋯ Moreover, intrathecal treatment with GF (0.73 nmol) attenuated the formalin paw injection-induced flinching, preferentially at the 2nd phase, that is known to be associated with the release of endogenous SP at the spinal cord. These data suggest that activation of spinal PKC is involved in the SP-mediated hyperalgesia. Thus, SP, which is released in the spinal cord subsequent to persistent stimulation of small sensory afferents after tissue injury, may contribute to spinal hyperexcitability and persistent pain by enhancement of PKC-mediated phosphorylation of target molecules such as NMDA receptors.
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The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. ⋯ Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.
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Reg Anesth Pain Med · Sep 2000
Randomized Controlled Trial Clinical TrialEffect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury. ⋯ Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers.