Effects of Thiopental and Its Optical Isomers on Nicotinic Acetylcholine Receptors

Background: With the exception of [gamma]-aminobutyric acidA (GABAA) receptors, the major molecular targets underlying the anesthetizing actions of thiopental have yet to be established. Neuronal nicotinic acetylcholine receptors (nAChRs) are closely related to GABAA receptors and hence might also be major targets. If so, they might be expected to be substantially inhibited by surgical concentrations (EC50 = 25 [mu]m) of thiopental and to display the same stereoselectivity as does general anesthesia.

Methods: Neuronal [alpha]4[beta]2, neuronal [alpha]7 and muscle [alpha][beta][gamma][delta] nAChRs were expressed in Xenopus oocytes. Peak acetylcholine-activated currents were measured at -70 mV using the two-electrode voltage clamp technique. Racemic thiopental and its two optical isomers were applied with and without preincubation and at high and low concentrations of acetylcholine.

Results: Inhibition of all three nAChRs was enhanced by preincubation with thiopental, a protocol that mimics the pharmacologic situation in vivo. Using 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 muscle [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 inhibiting the neuronal [alpha]4[beta]2 nAChR; interestingly, this is diametrically opposite to their stereoselectivity for general anesthesia.