Elsevier

Brain Research Bulletin

Volume 57, Issue 2, 15 January 2002, Pages 133-150
Brain Research Bulletin

Review article
The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia

https://doi.org/10.1016/S0361-9230(01)00740-7Get rights and content

Abstract

Nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily, that includes also gamma-amino-butiric-acidA, glycine, and 5-hydroxytryptamine3 receptors. Functional nicotinic acetylcholine receptors result from the association of five subunits each contributing to the pore lining. The major neuronal nicotinic acetylcholine receptors are heterologous pentamers of α4β2 subunits (brain), or α3β4 subunits (autonomic ganglia). Another class of neuronal receptors that are found both in the central and peripheral nervous system is the homomeric α7 receptor. The muscle receptor subtypes comprise of αβδγ (embryonal) or αβδε (adult) subunits. Although nicotinic acetylcholine receptors are not directly involved in the hypnotic component of anesthesia, it is possible that modulation of central nicotinic transmission by volatile agents contributes to analgesia. The main effect of anesthetic agents on nicotinic acetylcholine receptors is inhibitory. Volatile anesthetics and ketamine are the most potent inhibitors both at α4β2 and α3β4 receptors with clinically relevant IC50 values. Neuronal nicotinic acetylcholine receptors are more sensitive to anesthetics than their muscle counterparts, with the exception of the α7 receptor. Several intravenous anesthetics such as barbiturates, etomidate, and propofol exert also an inhibitory effect on the nicotinic acetylcholine receptors, but only at concentrations higher than those necessary for anesthesia. Usual clinical concentrations of curare cause competitive inhibition of muscle nicotinic acetylcholine receptors while higher concentrations may induce open channel blockade. Neuronal nAChRs like α4β2 and α3β4 are inhibited by atracurium, a curare derivative, but at low concentrations the α4β2 receptor is activated. Inhibition of sympathetic transmission by clinically relevant concentrations of some anesthetic agents is probably one of the factors involved in arterial hypotension during anesthesia.

Introduction

Historically the development of anesthesia has been associated with progress in surgery, both interacting in positive ways. At the beginning anesthesia was essentially empirical in its approach, based on the use of single pharmacological agents resulting in high toxicity. The skilled use of multiple agents with differential effects appeared early in the 20th century, and the use of opioids and curare-like agents as a supplement in general anesthesia became progressively more prominent promoting better analgesia and muscle relaxation, and lessening side effects. The development of a large spectrum of new agents further improved the practice of anesthesia. This provided a choice for the anesthetist in assuring that three major criteria were fulfilled necessary for adequate surgical anesthesia: antinociception (analgesia), unconsciousness (sedation or hypnosis), and decreased muscle tone (effective muscle relaxation). Although the major aim of anesthesia today is to insure patient safety and protection against stress, the situation is far from perfect. Furthermore, the mechanisms of anesthetic agents on the central nervous system (CNS) remain poorly understood. Despite this limited knowledge, anesthesia is widely employed as evidenced by a recent survey in France revealing that 13.5% of the population undergoes anesthesia every year [31]. For public safety and for scientific interest it is important to better understand the mechanisms underlying the anesthetic process, thus opening the way to the development of more selective and safer drugs for the future.

Until recently, a traditional view of the mechanisms of anesthesia, based on the Meyer-Overton correlation, (potency of general anesthetics correlates with their oil/gas partition coefficient), was that general anesthetics act by disrupting the lipid bilayer of nerve membranes [115]. However, accumulating evidence suggests that, at therapeutic concentrations, direct binding to receptor proteins is probably their main mechanism of effect [67]. For example, the activity of a soluble lipid-free enzyme, firefly luciferase, is inhibited by general anesthetics at concentrations close to their EC50 values [64]. The nature of the binding site of anesthetics remains, however, unclear: they may act directly on signaling proteins or indirectly through the lipid membrane surrounding these proteins (allosteric mechanism) 47, 65. Using optical isomers of pentobarbital (an oxybarbiturate analogue of thiopental) and isoflurane, stereospecific actions on ion channel proteins, but not on lipid bilayers, were observed 66, 117. Accordingly, direct binding to ligand gated ion channels (LGICs) are considered today the primary mechanism of action of anesthetic compounds [67]. The superfamily of LGICs includes the inhibitory gamma-aminobutiric acid (GABA)A, glycine, and the excitatory 5-hydroxytryptamine (5-HT3) and nicotinic acetylcholine receptor (nAChR) channels.

The major role of GABA-ergic transmission in the context of anesthetic action is well documented 67, 120, with most anesthetic agents having been shown to affect inhibitory transmission and enhance GABAA-receptor-mediated currents 67, 68. The action of general anesthetics, however, is not limited to the GABAA receptors, but includes other LGICs such as the glycine and nACh receptors [68]. Glutamate receptors, however, which do not belong to this superfamily, are insensitive to the majority of general anesthetics with the exception of ketamine and nitrous oxide (N2O) 91, 195. Although the role of nAChRs in the mechanism of anesthesia is less clear than for GABAA-receptors, it can be suspected that nAChRs in the CNS, through their modulation of inhibitory and excitatory transmission, could contribute to particular components of the anesthetic state such as amnesia, inattentiveness, and delirium.

Recent advances in molecular biology have characterized the neuronal homologues of the muscle nAChRs and it has been shown that these receptors display a differential sensitivity to anesthetic agents. Furthermore, the wide distribution of nAChRs in the central and peripheral nervous system (CNS and PNS) and also at the neuromuscular junction (NMJ) highlights their importance in autonomic regulation [175] and in neuromuscular transmission, both being crucial elements to consider in the practice of anesthesia. Pharmacological evidence indicates that nicotinic transmission is also involved in pain processing and antinociception [108], thus providing new alternatives in the development of analgesic agents.

The aim of this work is to summarize our current knowledge of the role and possible contribution of the nAChR system in the mechanisms of general anesthesia. The interactions between general anesthetics and nAChRs will be discussed, as well as the implications of these interactions for the function of muscle and neuronal nAChRs in the context of anesthesia. In addition, we will discuss the effect of neuromuscular blocking agents on the neuronal (but not muscle) nAChRs.

Section snippets

Structure and distribution

Nicotinic acetylcholine receptors are formed by the association of five subunits, each contributing to the pore lining. A subunit is composed by a large N-terminal domain of about 220 amino acids (AA), that contribute to the formation of the ligand binding domain, four transmembrane domains (MI to MIV), a large and variable cytoplasmic loop between MIII and MIV, and a small extracellular carboxyl terminal (Fig. 1A). The nAChRs subunits are broadly divided into an α type containing the

Effects of anesthetic agents on nAChRs

A large body of literature describes the effects of a wide variety of substances at muscle and neuronal nAChRs. However, for the scope of this review the focus will be on those compounds that are currently used for general anesthesia.

Inhalational anesthetics are one of the most important groups of drugs for anesthesiologists. A widely used index of their potency is the minimum alveolar concentration (MAC). For humans, MAC 1.0 is defined as the amount of an inhalational anesthetic needed to

Clinical implications

The effects of anesthetics and muscle relaxants on nicotinic transmission play a significant role in clinical anesthesia, because the inhibition or blockade of nAChRs may cause both wanted and unwanted effects during and after a general anesthesia. Peripheral effects include muscle relaxation and ganglion blockade, whereas CNS effects comprise modulation of behavior and nociception (Fig. 3).

Conclusion

Clinically relevant concentrations of volatile anesthetics and ketamine are potent inhibitors of both muscle and neuronal nAChR channels. Competitive inhibition, open channel block, allosteric mechanism, and increased desensitization have been reported. In most cases, the neuronal receptors are more sensitive than muscle receptors, with the exception of the homomeric α7 receptor. The major α4β2 brain receptor and α3β4 ganglionic receptor are inhibited even by subanesthetic concentrations of

Acknowledgements

This work was supported by Swiss National Science Foundation—No. 32-53863 to E.T., D.M., and D.B.

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