Neuropharmacology
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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.
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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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The rat hemisected spinal cord preparation was used to assess the role of different adrenoceptor subtypes on the modulation of nociceptive reflexes. These were elicited by trains of high intensity electrical stimuli delivered to a lumbar dorsal root. Responses were recorded from the corresponding ventral root in AC- and DC-amplification modes simultaneously. ⋯ Noradrenaline-induced depression of cumulative depolarisation was mimicked by the alpha2-adrenoceptor agonist UK 14,304. In addition, this compound produced inhibition of firing in responses to afferent stimulation. These results show that noradrenaline has bi-directional modulatory effects on nociceptive reflexes and indicate that selective activation of alpha1A- but not alpha1B/D-adrenoceptors mediate potentiation of spinal nociceptive reflexes.
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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.