Reply from Keith Miller

TINS-August1986 Sites of general anaesthesia SIR:

In a recent article addressing the question of whether lipids or proteins are the target for general anaesthetic action (TINS, February 1986), Keith Miller describes the allosteric action of barbiturates on G A B A receptors as an example of a 'hard' protein site that imposes 'structure-activity relations quite unlike those seen in general anaesthesia'. In fact, there is a much better correlation than he suggests. The relative potencies of a series of five barbiturates as potentiators of GABAA-receptor-mediated responses correlate very well with their relative potencies as general anaesthetics 1. The equi-effective concentrations of these barbiturates on the G A B A A receptor span a 50-fold range of concentrations in the aqueous medium but, when their partition into lipid is calculated, the equi-effective concentrations in lipid span less than a two-fold range. Thus, the fact that anaesthetics generally are

353 effective over a narrow range of concentrations in membranes irrespective of their aqueous potency does not preclude, in the case of barbiturates, an action on the GABAA receptor complex. The potential importance of this site is further increased by evidence that the steroidal anaesthetic alphaxalone also interacts with the GABAA receptor in a barbiturate-like manner 2. MICHAEL A. SIMMONDS

MRC Neuropharmacology Research Group, Department of Pharmacology, The School of Pharmacy, University of London, London WC1N lAX, UK.

References 1 Harrison, N. L. and Simmonds, M. A. (1983) Br. J. Pharmacol. 80, 387-394 2 Harrison, N. L and Simmonds, M. A. (1984) Bra/n Res. 323,287-292

Reply from Keith M i l l e r SIR:

Simmonds's point is well taken, but the situation at the G A B A receptor is quite

complex, with a number of modulatory sites being postulated 1. I would point out in reply that the postulated barbiturate binding site on the G A B A receptor distinguishes between the enantiomers of barbiturates, and as such clearly possesses a degree of structural specificity. For example, the ( - ) isomer of MPPB (N-methyl-5phenyl-propyl-barbitufic acid) displaces the 'cage convulsant' [35S]TBPT (t-butylbicyclophosphorothionate) with six and a half times the potency of the (+) isomer 1. While the GABAA receptor response that he examined might be mediated by a different site, there certainly is a 'hard' site for barbiturates. KE1TH W. MILLER

Departments of Anaesthesia and Pharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Reference 1 Ticku, M. K. and Rastogi, S. K. (1986) in

Molecular and Cellular Mechanisms of Anesthet/cs (Roth, S. H. and Miller, K. W., eds), pp. 179-187, Plenum Press