Effects of thiopental and its optical isomers on nicotinic acetylcholine receptors

Background: With the exception of gamma-aminobutyric acid, (GABA(A)) recept ors, the major molecular targets underlying the anesthetizing actions of th iopental have yet to be established. Neuronal nicotinic acetylcholine recep tors (nAChRs) are closely related to GABA(A) receptors and hence might also be major targets. If so, they might be expected to be substantially inhibi ted by surgical concentrations (EC50 = 25 mu M) of thiopental and to displa y the same stereoselectivity as does general anesthesia. Methods: Neuronal alpha 4 beta 2, neuronal alpha 7 and muscle alpha beta ga mma delta nAChRs were expressed in Xenopus oocytes, Peak acetylcholine-acti vated currents were measured at -70 mV using the two-electrode voltage clam p technique. Racemic thiopental and its two optical isomers were applied wi th and without preincubation and at high and low concentrations of acetylch oline. Results: Inhibition of all three nAChRs was enhanced by preincubation with thiopental, a protocol that mimics the pharmacologic situation in vivo. Usi ng this protocol, inhibition was further enhanced by high concentrations of acetylcholine, with IC50 = 18 +/- 2, 34 +/- 4, and 20 +/- 2 mu M (mean +/- SEM) thiopental for the neuronal alpha 4 beta 2, neuronal alpha 7 and musc le alpha beta gamma delta nAChRs, respectively, with Hill coefficients near unity. Neither the neuronal alpha 7 nor the muscle alpha beta gamma delta nAChR differentiated between the optical isomers of thiopental. However, R( +)-thiopental was significantly more effective than the S(-) isomer at inhi biting the neuronal alpha 4 beta 2 nAChR; interestingly, this is diametrica lly opposite to their stereoselectivity for general anesthesia. Conclusions: Both central neuronal and peripheral muscle nAChRs can be subs tantially inhibited by thiopental at surgical EC50 concentrations but with either no stereoselectivity or one opposite to that for general anesthesia, Thus, nAChRs are probably not crucial targets for producing thiopental ane sthesia, although nAChRs may play a part in the side effects produced by th is agent.