British journal of pharmacology
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Different alpha subunits of human gamma-aminobutyric acid type A (GABA(A)) receptors were transiently expressed together with beta(3) and gamma(2) subunits in Xenopus oocytes to examine the interactions of various GABA(A) agonists and representative allosteric modulators. Chloride currents elicited by agonists were measured using two electrode voltage clamp electrophysiology. Where compounds behaved as full agonists, i.e. ⋯ I(max) values for piperidine-4-sulphonic acid (P4S) on alpha(1)beta(3)gamma(2), THIP on alpha(3)beta(3)gamma(2), and 5-(4-piperidyl)isothiazol-3-ol (thio-4-PIOL) on alpha(2)beta(3)gamma(2) and alpha(5)beta(3)gamma(2) GABA(A) receptors were increased by chlordiazepoxide, while that for P4S on alpha(1)beta(3)gamma(2) receptors was decreased by DMCM. The I(max) values for partial agonists were also enhanced by pentobarbitone, the neurosteroid allopregnanolone and loreclezole irrespective of receptor subtype or the nature of the partial agonist. In the light of models of ligand-gated ion channel receptor activation we suggest two possible mechanisms of action for the effects of allosteric modulators on partial agonist receptor activation: either selective modulation of agonist affinity for the open/closed state, or direct modulation of the gating process itself.
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The effects of convulsant drugs, and of thyrotropin releasing hormone (TRH), were examined on the general anaesthetic actions of ketamine, ethanol, pentobarbitone and propofol in mice. The aim was to investigate the possibility of selective antagonism, which, if seen, would provide information about the mechanism of the anaesthesia. The general anaesthetic effects of ketamine were unaffected by bicuculline; antagonism was seen with 4-aminopyridine and significant potentiation with 300 mg kg(-1) NMDLA (N-methyl-DL-aspartate). ⋯ Bicuculline did not alter the anaesthetic actions of propofol, while potentiation was seen with NMDLA and 4-aminopyridine. TRH had no significant effect on propofol anaesthetic, but Bay K 8644 at 1 mg kg(-1) significantly potentiated the anaesthesia. These results suggest that potentiation of GABA(A) transmission or inhibition of NMDA receptor-mediated transmission do not appear to play a major role in the production of general anaesthesia by the agents used.
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Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats. Subcutaneous administration of 50 microl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection. ⋯ However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation. These results indicate that mu and delta opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to delta agonists in the hyperalgesia model suggests that delta opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation.