Neuropharmacology
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The finding that serotonin (5-HT) can modulate dopamine (DA) and norepinephrine (NE) release in the brain has led us to hypothesize that fluoxetine, a selective 5-HT reuptake inhibitor, may influence the ability of bupropion, a preferential DA and NE dual reuptake inhibitor, to modulate extracellular DA and NE concentrations in some brain areas. The present study was designed to evaluate this hypothesis by assessing the effects of fluoxetine on bupropion-induced changes in extracellular monoamine concentrations by means of in vivo microdialysis. Three mesocorticolimbic areas including hypothalamus (Ht), prefrontal cortex (Pfc) and nucleus accumbens (Acb) were selected based on their relevance to depression and antidepressant actions. ⋯ Bupropion did not significantly affect the extracellular 5-HT concentrations in all the 3 brain areas tested. In summary, the present study demonstrated that bupropion can increase extracellular DA and NE concentrations in several mesocorticolimbic areas, which may have an impact on bupropion's antidepressant actions. Furthermore, fluoxetine can potentiate the bupropion-induced DA and NE increases, which may produce more effective and rapid antidepressant actions.
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The effects of the peripherally restricted opioid agonist loperamide were compared to those of morphine in the formalin test in rats. Both loperamide and morphine were efficacious in producing antihyperalgesia after both subcutaneous and intracisternal administration. The antihyperalgesic effects of peripherally administered loperamide and morphine were antagonized by both naloxone and its quaternary derivative naloxone methiodide. ⋯ However, neither the kappa-receptor selective antagonist nor-binaltorphimine nor the delta-receptor selective antagonist naltrindole blocked the effects of either opioid agonist. The present results are consistent with the interpretation that the antihyperalgesic effects of opioid agonists can have both a peripheral and a central component of action, and that the peripheral component of action is sufficient to produce antihyperalgesia in the formalin test after peripheral administration. The present results provide further evidence that peripherally restricted opioid agonists might provide clinically useful treatment of some pain states, in particular pain states that might involve sensitization of peripheral nociceptors.
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Comparative Study
Evidence for the participation of kinins in Freund's adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice.
Experiments were designed to investigate the role of kinin B(1) and B(2) receptors in Freund's adjuvant (CFA)-induced inflammation and nociception responses by the use of B(1) and B(2) null mutant mice. Intradermal (i.d.) injection of CFA produced time-dependent and marked hyperalgesic responses in both ipsilateral and contralateral paws of wild-type mice. Gene disruption of the kinin B(2) receptor did not interfere with CFA-induced hyperalgesia, but ablation of the gene of the B(1) receptor reduced the hyperalgesia in both ipsilateral (48+/-13%, at 12 h) and contralateral (91+/-22%, at 12 h) paws. ⋯ In mice lacking B(2) receptor, the earlier stage of the CFA-induced paw oedema (6 h) was significantly greater compared with the wild-type animals, an effect which was almost completely reversed (76+/-5%) by des-Arg(9)-[Leu(8)]-BK. This data demonstrates that kinin B(1) receptor, but not B(2) receptor, exerts a critical role in controlling the persistent inflammatory hyperalgesia induced by CFA in mice, while B(2) receptor appears to have only a minor role in the amplification of the earlier stage of CFA-induced paw oedema formation. The results of the present study, taken together with those of previous studies, suggest that B(1) receptor antagonists represent a potential target for the development of new drugs to treat persistent inflammatory pain.
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Recent interest has focused on the potential of cannabinoids as novel analgesics. The aim of the present study was to investigate the effect of a potent cannabinoid agonist, HU210, on somatosensory transmission in a model of neuropathic pain. Here, the effects of spinal versus systemic administration of HU210 on noxious and innocuous evoked responses of spinal neurones of nerve injured (selective ligation of spinal nerves L5-L6) and sham operated rats were compared 14-17 days post-surgical intervention. ⋯ HU210 (60 microg/kg) inhibited the overall C-fibre evoked response (54+/-8% of control, p<0.01), post-discharge response (28+/-12% of control, p<0.01), and Adelta-fibre evoked (48+/-5% of control p<0.01) responses of spinal neurones. In nerve injured rats, systemic administration of HU210 did not significantly reduce C- or Abeta-fibre evoked responses of spinal neurones. This study demonstrates plasticity of the spinal cannabinoid receptor system following peripheral nerve injury.
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gamma-Aminobutyric acid type A (GABA(A)) receptors are an important target for general anesthetics in the central nervous system. Site-directed mutagenesis techniques have identified amino acid residues that are important for the positive modulation of GABA(A) receptors by general anesthetics. In the present study, we investigate the role of an amino acid residue in transmembrane (TM) domain 3 of the GABA(A) receptor beta(2) subunit for modulation by the general anesthetic 2,6-diisopropylphenol (propofol). ⋯ In contrast, substitution of methionine 286 by alanine, cysteine, glutamate, lysine, phenylalanine, serine, or tyrosine was permissive for potentiation of GABA responses and direct activation by propofol. Using propofol analogs of varying molecular size, we show that the beta(2)(M286W) mutation resulted in a decrease in the 'cut-off' volume for propofol analog molecules to enhance GABA responses at GABA(A) alpha(1)beta(2)gamma(2s) receptors. This suggests that mutation of M286 in the GABA(A) beta(2) subunit alters the dimensions of a 'binding pocket' for propofol and related alkylphenol general anesthetics.