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R Nadeson, Z Guo, V Porter, JP Gent and CS Goodchild
Department of Anesthesia, Monash University, Clayton, Victoria, Australia.
Experiments were performed on rats with lumbar subarachnoid catheters, using four agonist drugs [gamma-aminobutyric acid (GABA), muscimol, midazolam and 5-hydroxytryptamine (5-HT)] and two GABA(A) antagonists (bicuculline and SR-95531) given intrathecally. All four agonists caused dose-related antinociception assessed by the electrical current threshold test. These effects were spinally mediated because the agonists caused increases in nociceptive thresholds in the skin of the tail and not the neck. In the same experiments, 5-HT and GABA caused simultaneous increases in tail-flick latency and electrical current thresholds in the tail. Both GABA(A) antagonists caused dose-related suppression of the antinociceptive effects of equieffective doses of all four agonists. Tail-flick latency increases caused by 5-HT were not suppressed by bicuculline in the same experiments in which bicuculline had suppressed the electrical current threshold effects of intrathecal 5-HT. The log dose-response curves for both antagonists for suppression of GABA effects were coincident, having a very shallow slope and covering the whole range of doses effective against the other agonists. The two GABA(A) antagonists were very different in relative potency for suppression of the spinally mediated antinociceptive effects of the other three agonists. The rank order of potency for bicuculline suppression of the effects of equieffective doses of the other agonists was muscimol > 5-HT > midazolam, whereas the rank order for SR-95531 was muscimol >> midazolam > 5-HT. We conclude that there exist in the spinal cord at least three different GABA(A) receptors responsible for spinally mediated antinociception caused by intrathecal injections of midazolam, muscimol and 5-HT. These are all targets for endogenous GABA.
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