Articles: hyperalgesia.
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Journal of neurochemistry · Mar 2005
Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization.
Antagonist studies show that spinal p38 mitogen-activated protein kinase plays a crucial role in spinal sensitization. However, there are two p38 isoforms found in spinal cord and the relative contribution of these two to hyperalgesia is not known. Here we demonstrate that the isoforms are distinctly expressed in spinal dorsal horn: p38alpha in neurons and p38beta in microglia. ⋯ In these rats, down-regulation of spinal p38beta, but not p38alpha, prevented nocifensive flinching evoked by intraplantar injection of formalin and hyperalgesia induced by activation of spinal neurokinin-1 receptors through intrathecal injection of substance P. Both intraplantar formalin and intrathecal substance P produced an increase in spinal p38 phosphorylation and this phosphorylation (activation) was prevented when spinal p38beta, but not p38alpha, was down-regulated. Thus, spinal p38beta, probably in microglia, plays a significant role in spinal nociceptive processing and represents a potential target for pain therapy.
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Comparative Study
Potentiation of spinal N-methyl-D-aspartate-mediated nociceptive transmission by cocaine-regulated and amphetamine-regulated transcript peptide in rats.
The present study examined the effects of cocaine-regulated and amphetamine-regulated transcript peptide (CARTp) fragment 55-102, on N-methyl-D-aspartate (NMDA)-mediated nociceptive transmission in vivo and in vitro. In-vivo experiments were conducted in Sprague-Dawley rats to evaluate the effects of CARTp on thermal hyperalgesia induced by NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Intrathecal NMDA (1, 2, 4 nmol) or AMPA (0.5, 1, 2 nmol) dose-dependently decreased the tail-flick latency. ⋯ The in-vitro effects of CARTp on NMDA-induced or AMPA-induced depolarizations in substantia gelatinosa neurons were studied in rat spinal cord slices. CARTp (100, 300 nM), which caused no significant change of membrane potentials, increased the amplitude of NMDA-induced depolarizations in substantia gelatinosa neurons with little effect on AMPA-induced depolarizations. The present study demonstrates that exogenously applied CARTp selectively facilitates NMDA receptor-mediated nociceptive transmission.
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Comparative Study
Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats.
Spinal noradrenaline (NA) released in response to noxious stimuli may play an important role in suppression of nociceptive transmission. Here, we investigated the efficacy of a competitive NA transporter inhibitor (reboxetine) and a noncompetitive NA transporter inhibitor peptide, Xen2174, isolated from the Pacific cone snail, to treat tactile hypersensitivity following paw incisional surgery. Male Sprague-Dawley rats were anesthetized, an incision of the plantar aspect of the hind paw was performed, and withdrawal threshold to von Frey filaments near the surgical site determined. ⋯ The anti-hypersensitivity effect of 10 microg of Xen2174 was totally blocked by the alpha2-adrenoceptor antagonist, idazoxan, and partially blocked by the muscarinic antagonist, atropine. These data suggest that selective NA transporter inhibition suppresses post-incisional hypersensitivity through a different mechanism from that of neuropathic pain, since we previously reported that reversal of hypersensitivity by intrathecal clonidine, an alpha2-adrenoceptor agonist, following spinal nerve ligation is completely blocked by intrathecal atropine. Finally, these data suggest that intrathecal administration of Xen2174 at the time of spinal anesthesia might produce postoperative analgesia in humans.
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Randomized Controlled Trial Comparative Study Clinical Trial
Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect.
The aim of this study was to investigate the effect of dextromethorphan (DM) 0.5 mg/kg administered intravenously (i.v.) on hyperalgesia and pain after a tissue injury in human volunteers, and to describe the relationship between pharmacokinetic and pharmacodynamic data. The heat-capsaicin sensitisation model, a well-established experimental hyperalgesia model was induced in 24 healthy, male volunteers aged 21-35 years. The subjects received i.v. ⋯ The pharmacokinetic-pharmacodynamic relationship showed a large inter-subject variation with a mean delay in effect of nearly 2 h in relation to peak serum concentration. The results strongly indicate that DM is an anti-hyperalgesic drug. The delay in effect may be explained by several mechanisms and suggests that timing of DM administration is an essential factor for using the drug in clinical settings.
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J. Pharmacol. Exp. Ther. · Feb 2005
An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance.
We determined whether the i.t. administration of an 18-mer phosphodiester antisense oligodeoxynucleotide (ODN) that reduces the expression of the rat NMDAR1 subunit of the N-methyl-d-aspartate (NMDA) receptor would affect nociceptive behaviors and prevent the development of morphine tolerance. Rats received 5 microl of i.t. saline, 30 nM antisense, or mismatch ODN twice a day for 5 days (NMDA-induced nociception, NMDA-induced thermal hyperalgesia, NR1 mRNA, and ligand binding studies) or for 3 days (formalin study). For the tolerance study, 5 days of ODNs or saline were followed by 3 days of concurrent administration of ODNs or saline (twice a day) and i.t. morphine (three times a day). ⋯ The coadministration of antisense with increasing doses of i.t. morphine for 3 days attenuates the development of morphine tolerance. These results demonstrate that an in vivo antisense targeting of the NMDAR1 subunit results in antihyperalgesic effects and a partial blockade of spinal morphine tolerance. They provide additional support for the critical role of the NMDA receptor in these forms of spinal nociception and in the development of morphine tolerance and suggest the potential therapeutic utility of this approach.