2005 Annual Scientific Meeting - CLICK FOR PROGRAMME

Anaesthetic Drugs – where do they work?

 Dr Cameron Weir, Consultant Anaesthetist & Senior Lecturer,

Ninewells Hospital & Medical School, Dundee DD1 9SY

c.j.weir@dundee.ac.uk

Although general anaesthetics play a crucial role in modern medicine, the mechanism(s) responsible for their dramatic clinical effects have, until now, remained elusive. My presentation will summarise the remarkable developments that have occurred in general anaesthetic research over the past two decades. Rather than acting non-specifically to disrupt lipid membranes, it appears that general anaesthetics target certain CNS proteins in a highly selective manner. For example, most general anaesthetics modulate the activity of a family of genetically related receptors (transmitter-gated ion channels) within the CNS. The Neurosciences Institute in Dundee has demonstrated that one of these receptors (the GABA_A receptor) is particularly sensitive to many clinically used intravenous (iv) general anaesthetics. Indeed, we have demonstrated that this anaesthetic interaction is governed by a single amino acid, within a protein composed of over 2000 amino acids. By engineering mice that carry a mutation of this crucial amino acid we, in collaboration, have shown categorically that distinct subtypes of GABA_A receptor mediate the sedative (b₂ subunit) and hypnotic (b₃  subunit) actions of the intravenous anaesthetic etomidate.

This work is helping to clarify whether the identified amino acids contribute to an anaesthetic binding pocket within the GABA_A receptor and ultimately these studies should aid the future design of novel GABA_A receptor subtype selective anaesthetics, that are clinically safer with a reduced risk of side effects.

References

1.      Belelli D, Pistis M, Peters JA, Lambert JJ. General anaesthetic action at transmitter-gated inhibitory amino acid receptors. Trends Pharmacol Sci 1999; 20(12):496-502.

2.      Weir CJ, Wildsmith JAW. How do General Anaesthetics Work? The case for GABA_A Receptor Modulation. Preparing for the Primary FRCA Bulletin of the Royal College of Anaesthetists 2001;5:204-207.

3.      Reynolds DS, Rosahl TW, Cirone J, O'Meara GF, Haythornthwaite A, Newman RJ et al. Sedation and anesthesia mediated by distinct GABA_A receptor isoforms. J Neurosci 2003; 23(24):8608-8617.

4.      Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA_A receptor b₃  subunit. FASEB J 2003; 17(2):250-252.

5.     Weir CJ, Ling AT, Belelli D, Wildsmith JA, Peters JA, Lambert JJ. The interaction of anaesthetic steroids with recombinant glycine and GABA_A receptors. Br J Anaesth 2004; 92(5):704-711.

6. Hemmings HC, Jr., Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005; 26(10):503-510.