Neuropharmacology
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Clinical reports have described a long-lasting relief in neuropathic pain patients treated with NMDA receptor antagonists; it is unclear, however, what mediates this effect. In this work, we have used two NMDA antagonists of different class to investigate if the antiallodynic effects in a rat neuropathy model can outlast their in vivo NMDA antagonism. Both the uncompetitive NMDA antagonist ketamine and the glycine(B) antagonist MRZ 2/576 inhibited neuronal responses to iontophoretic NMDA in anaesthetised rats with the time course consistent with their known pharmacokinetics (t(1/2) approximately 10-12min, similar in control and nerve-injured rats). ⋯ The duration of centrally mediated side effects of ketamine and MRZ 2/576 was short, similar to the in vivo NMDA antagonism. We speculate that NMDA receptor blockade may down-regulate the central sensitisation triggered by nerve injury, resulting in a long-lasting antiallodynic effect. Development of short-acting NMDA antagonists could represent a strategy for improving their tolerability.
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Comparative Study
Effects of chronic nicotine administration and its withdrawal on striatal FosB/DeltaFosB and c-Fos expression in rats and mice.
DeltaFosB, a member of Fos family of transcription factors, is implicated in behavioural responses and synaptic plasticity induced by abused drugs. We studied the expressions of FosB/DeltaFosB and c-Fos immunohistochemically in two dopaminergic brain areas, nucleus accumbens (NAcc) and caudate-putamen (CPu). In mice neither 2- nor 7-week oral nicotine treatment induced expression of long-lived DeltaFosB isoforms although during the treatment in the NAcc FosB/DeltaFosB expression was increased as was c-Fos in the CPu. ⋯ Thus, in rats repeated nicotine administration seems mainly affect the NAcc paralleling with the evidence that nicotine stimulates preferentially mesolimbic dopamine system. Also, repeated nicotine induced behavioural sensitization in rats agreeing with suggested role of DeltaFosB in the development of psychomotor sensitization. However, in mice given nicotine via drinking fluid although striatal fosB and c-fos were activated by nicotine even after 7-week treatment no evidence of accumulation of long-lived DeltaFosB was found suggesting perhaps a species difference or more likely a role for the manner of administration.
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Mechanical hyperalgesia induced in rat paws by carrageenan (250microg) was modified by pre-treatment with three selective inhibitors of cyclo-oxygenase-2 (COX-2); celecoxib, rofecoxib and SC236. These inhibitors raised the nociceptive threshold above the normal, non-inflamed, level, inducing a state of hypoalgesia. Such hypoalgesia was observed in different strains of rat (Holtzman, Wistar and Sprague-Dawley) and after different modes of administration of the COX-2 inhibitor (locally, in the paw, or systemically). ⋯ Pre-treatment with naltrexone (3mg kg(-1)), an opioid receptor antagonist, did not affect carrageenan-induced hyperalgesia but abolished the hypoalgesic effects of COX-2 inhibitors, without diminishing the anti-hyperalgesic effect of indomethacin. In rats made tolerant to the anti-nociceptive effects of morphine, all anti-nociceptive effects of SC236 were abolished but the anti-hyperalgesic effects of indomethacin or SC 560 were unaffected. We conclude that, in our model of inflammatory hyperalgesia, the anti-nociceptive effect of selective COX-2 inhibitors involved the participation of endogenous opioids.