Sex difference in response to alphaxalone anaesthesia may be oestrogen dependent

Abstract

The steroid anaesthetic Althesin (Glaxo), which is a mixture of two C₂₁ steroids, alphaxalone (3α-hydroxy-5α-pregnane-11, 20-dione—the active compound) and alphadolone acetate (21-acetoxy-3α-hydroxy-5αpregnane-11, 20-dione), has been especially useful for the study of forebrain-autonomic¹ and neuroendocrine functions^2–5. As determined by the loss of the righting reflex, Child et al.⁶ found no sex difference in the anaesthetic dose of Althesin administered intravenously (i.v.). However, in our neuroendocrine studies^2–5 in which the anaesthetic was adminstered intraperitoneally (i.p.) and at dosage sufficient to produce surgical anaesthesia and analgesia, we observed a sex difference in the efficacy of Althesin. This may explain the difficulties that have been encountered in obtaining adequate anaesthesia (blockade of the somatomotor response to pain) with Althesin. Here we report, using cortical electroencephalography, that Althesin is a more potent anaesthetic than either sodium pentobarbitone or urethane, and that anaesthesia in the male rat requires about four times more Althesin (administered i.p.) than in the female. This sex difference is age dependent, can be abolished by administering oestrogen to the male, does not depend on sexual differentiation of the brain, and cannot be attributed to a sex difference in the metabolic clearance rate of alphaxalone. These results, taken together with those of Richards and Hesketh⁷, suggest that the effect of alphaxalone may be mediated by interactions with synaptic membranes that are more specific than simply a generalized change in membrane structure, and that these interactions are affected by sex steroids.