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 (3 alpha-hydroxy-5 alpha-pregnane-11, 20-dione--the active compound) and alphadolone acetate (21-acetoxy-3 alpha-hydroxy-5 alpha-pregnane-11, 20-dione), has been especially useful for the study of forebrain-autonomic and neuroendocrine functions. As determined by the loss of the righting reflex, Child et al. found no sex difference in the anaesthetic dose of Althesin administered intravenously (i.v.). However, in our neuroendocrine studies in which the anaesthetic was administered 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 alphaxolone. These results, taken together with those of Richards and Hesketh, 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.

Oestradiol-17β Increases the Firing Rate of Antidromically Identified Neurones of the Rat Neostriatum

“…Recent work suggests that an interaction may occur be tween some anaesthetic agents and oestrogen [13]. It is pos sible that such an interaction between halothane (employed as the anaesthetic here) and oestrogen is responsible for the differences in the neuronal activity seen.…”

“…However, the presence of oestrogen seems to potentiate anaesthesia [at least with Althesin; ref. 13], and so would be expected to reduce neuronal firing. The increase in activity which we observed is thus unlikely to be due to an enhance ment of the anaesthesia by E2.…”

The G. W. Harris Lecture Steroid Control of Brain and Pituitary Function

“…The dose of alphaxalone necessary to produce surgical anaesthesia in male rats gradually increases with age until in adulthood it is about 4 times that in female ( Fig. 8; Fink, Sarkar, Dow, Dick, Borthwick, Malnick & Twine, 1982 c). This can be reversed by castration and oestrogen treatment of the male when adult (Fig.…”

“…This rapid action of alphaxalone raises two important questions. First, it challenges present concepts of the mechanism of action of anaesthetics in that specific protein receptors may be involved (Fink et al 1982 c;Evers, Berkowitz & d'Avignon, 1987;Frank & Lieb, 1987); but this is a subject for a separate review. Secondly, the anaesthetic action of alphaxalone is far too fast to be accounted for by an action on the genome.…”

Comparison of the Effects of Althesin and Sodium Pentobarbitone on the Regional Uptake of 2-Deoxyglucose by the Brain and Pituitary Gland of the Rat: Selective Effects on Pars intermedia

“…General anaesthesia induced by barbiturates, ether and chloral hy drate is associated with reductions in glucose utilization, especially in grey matter [12,13,24] The steroid anaesthetic Althesin® (Glaxo), a mixture of two C21 steroids, alphaxalone (3a-hydroxy-5a-pregnane-11,20-dione -the active compound) and aiphadolone ace tate (21-acetoxy-3a-hydroxy-5a-pregnane-l 1,20-dione) has been used extensively in neuroendocrine studies [10]. Al thesin does not block either the spontaneous ovulatory surge of luteinizing hormone (LH) or the associated surge of Received: May 26,1983 Accepted after revision: August 17, 1983 LH-releasing hormone (LHRH) [3,19,22], Sodium pento barbitone, by contrast to Althesin, blocks both of these surges [7,19,22].…”