PubMed · 532930
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S Mehta. 1979. Sensitivity testing for Althesin.. https://doi.org/10.1111/j.1365-2044.1979.tb08552.x
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1. Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2. The 5-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3. Pretreatment with the 5-HT(2) receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT(2A) receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT(2B/C) receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4. Pretreatment with the peripherally acting 5-HT(2) receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5. These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT(2A) receptor-subtype, but that 5-HT(2B/C) receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.
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Studies have shown that the steroid anaesthetic alphaxalone positively modulates gamma-aminobutyric acid (GABA) receptors in vitro. It has also been reported that positive modulation of GABA(A) receptors in the rat spinal cord can produce antinociception in vivo. This present study looks at the interaction of an intraperitoneal injection (i.p.) of the steroid anaesthetic combination Saffan (alphaxalone 9 mg/ml, alphadolone acetate 3 mg/ml) with GABA(A) receptors in the spinal cord. Full recovery from anaesthesia induced by Saffan 2 ml/kg i.p., as assessed by the rotarod test, occurred after 28.78 +/- 0.86 min. Residual antinociceptive effects were assessed by application of electrical current at two skin sites (neck and tail) and also tail withdrawal from noxious heat. Residual antinociception was observed at both skin sites assessed by the electrical test but not when assessed by noxious heat. The antinociceptive effects in the tail but not the neck were suppressed by intrathecal administration of GABA(A) antagonists (bicuculline and SR-95531). In a separate group of experiments alphaxalone and alphadolone were given i.p. individually at the same doses that were given when formulated in Saffan. Alphaxalone produced sedative and anaesthetic effects with no antinociception. Alphadolone caused no sedation but it did cause antinociceptive effects equal in magnitude to those produced by Saffan. We conclude that Saffan produces antinociception in rats when given i.p. by an interaction with spinal GABA(A) receptors. Furthermore, this antinociception is due to the alphadolone content of the neurosteroid anaesthetic and not the alphaxalone.