Anesthetic-induced immobility: neuronal nicotinic acetylcholine receptors are no longer in the picture.

Abstract

C onsensus concerning the relevant targets for volatile anesthetics is far from being reached: even cherished proteins of long standing, such as -aminobutyric acid type A (GABAA) receptors, have their determined detractors as well as staunch defenders. In addition to accumulating evidence indicating anesthetic effects on the favorite candidate proteins, it is necessary to determine the in vivo relevance of such effects, to try to eliminate neuronal players that do not mediate a specific anesthetic effect. Several compounds that fail to follow the Meyer-Overton rule (1,2) have been proposed as useful tools to this end. These halogenated alkanes are structurally related to well known anesthetics, and possess oil/gas partition coefficients that, according to the rule, should guarantee them anesthetic capabilities. But these compounds do not go by the book: they are unable to induce immobility at predicted minimum alveolar anesthetic concentrations (MACs), they do not decrease desflurane MAC when coapplied (3), and they have convulsant properties (3,4). The most studied nonimmobilizer is 1,2-dichlorohexafluorocyclobutane (F6, also called 2N). It also differs from anesthetics in that it does not affect thermoregulation (5), and does not depress breathing (conversely, it is a respiratory stimulant) (6). There is one important anesthetic quality that F6 retains: it suppresses learning (7,8), in a way not attributed to an alteration in pain perception (8). So the Meyer-Overton rule stands corrected: lipophilicity is not the only determinant of anesthetic capability; hydrophilicity must also be considered. There is considerable evidence that conventional anesthetics act at an interface between water/membrane/protein, so both hydrophilic and lipophilic characteristics are necessary to exert their effects. Nonimmobilizers do not possess the right combination of hydrophilicity and lipophilicity that allows them to concentrate at the water-membrane interface; instead, they accumulate in the membrane hydrocarbon core (9). Therefore, they cannot access and/or interact with the “immobility” sites. However, they can bind to a hydrophobic site to exert amnesic effects (10). A specific site for mediating even the convulsant effect seems likely in light of the differential effect of cis and trans isomers of F6 (11). Nonimmobilizers have been tested on several major candidates for anesthetic targets, namely, ligandgated ion channels (GABAA, glycine, serotonin-3, glutamate, and neuronal nicotinic acetylcholine receptors [nAChRs]) and G protein-coupled receptors (12), as well as on potassium channels (13,14), expressed in Xenopus laevis oocytes. F6 inhibits serotonin-2A currents (15), as well as muscarinic M1 receptor currents (16), so these G protein-coupled receptors are not likely to be involved in the immobilizing effect of volatile anesthetics. However, for all other receptors, nonimmobilizers have been reported not to have any appreciable effect and thus have not eliminated these ligand-gated ion channels as mediators of immobility. In nonneuronal nAChRs, F6 proved to have similar effects to classical anesthetics, either quantitatively smaller in Torpedo nAChR (17) or equally active in mouse muscle nAChRs (18). For neuronal nAChRs, the picture appears more complicated: as already mentioned, a study on human neuronal nAChRs reported no effect of F6 in several subtype combinations expressed in X. laevis oocytes (19), whereas another report found inhibition of nAChRs present in PC12 cells and in medial habenula neurons (20). In this issue of Anesthesia & Analgesia, Dr. Raines’ group (21) from Harvard Medical School reports inhibition of both rat and human neuronal nAChRs by F6. This is not only an important finding by itself, but it also settles the controversy between the earlier reports on nAChRs, and the reason behind the previous discrepancy raises an important issue in anesthetic research. Supported in part by Grant GM47818 from the National Institutes of Health. Accepted for publication June 4, 2002. Address correspondence to Cecilia M. Borghese, PhD, WCAAR, University of Texas at Austin, 2500 Speedway, MBB 1.124, Austin, TX 78712 1095. Address e-mail to cborghese@mail.utexas.edu. Address reprint requests to R. Adron Harris, PhD, at the same address.