Neuropharmacology
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Comparative Study
Interactions between CB1 cannabinoid and mu opioid receptors mediating inhibition of neurotransmitter release in rat nucleus accumbens core.
We examined the occurrence of functional interactions between CB1 cannabinoid and mu opioid receptors in the core of rat nucleus accumbens (NAc core). To that end, receptor-mediated inhibition of depolarization (4-aminopyridine)-induced [3H]glutamate release and glutamate (NMDA) receptor-stimulated [14C]acetylcholine (ACh) and [3H]GABA release was studied in superfused NAc core slices. The inhibitory effects of the mu receptor agonist morphine and the CB1 receptor agonist HU210 on the release of these neurotransmitters were selectively antagonized by the mu receptor antagonist naloxone and the CB1 receptor antagonist SR141716A, respectively. ⋯ Finally, the apparent allosteric interaction between antagonists was also observed regarding the effects of other receptor-selective agonists and antagonists at mu opioid and CB1 cannabinoid receptors (mediating inhibition of NMDA-induced [3H]GABA release) and must therefore be a unique property of the receptors involved. These data suggest the existence of physically associated mu opioid and CB1 cannabinoid receptors, whereby activation of these receptors results in either a non-additive (glutamate release) or a synergistic (GABA release) effect. It is proposed that these allosterically interacting mu and CB1 receptors in the NAc core may represent G-protein coupled heterodimeric receptor complexes.
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Comparative Study
Treatment with valproate after status epilepticus: effect on neuronal damage, epileptogenesis, and behavioral alterations in rats.
Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. ⋯ However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the dentate hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.
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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.