Is a new paradigm needed to explain how inhaled anesthetics produce immobility?

Abstract

A paradox arises from present information concerning the mechanism(s) by which inhaled anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which inhaled anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, gamma-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

Figure 1

This graph indicates the fraction of MAC for each anesthetic of a pair that, in combination, produces immobility in response to noxious stimulation in rats. Each anesthetic pair was usually chosen because the two anesthetics differed in their capacities to inhibit or enhance the response of a specific channel (e.g., cyclopropane minimally enhances the response of gamma-aminobutyric acid (GABA)_A receptors to GABA, whereas halothane markedly enhances the response). The sum of the fractional contributions never was less than 0.9, an a priori value assigned as the boundary between additivity and synergism (i.e., no pair acted synergistically). The data are taken from Eger et al.

Figure 2

In rats, MAC for various anesthetics was determined in the presence of intrathecal infusions of strychnine [a glycine receptor blocker; left panel] or picrotoxin [a gamma-aminobutyric acid (GABA)_A receptor blocker; right panel]. For infusions that produced maximal increases in MAC, the increases correlated with the capacity of particular anesthetics to enhance the response of glycine receptors in vitro but did not correlate with the capacity of particular anesthetics to enhance the response of GABA_A receptors in vitro (the in vitro capacity is indicated for each abcissa). Such results are consistent with a role for glycine receptors as the mediators of the anesthetic effect of some (e.g., halothane – see open circles) but not other (e.g., cyclopropane – see open triangles) anesthetics. Data for isoflurane are shown as closed diamonds, and data for isoflurane are shown as open circles. Such results also are not consistent with a role for GABA_Areceptors as mediators of immobility.

Figure 3

TREK-1 knockout mice have greater MAC values than their wild-type littermates. The upper graphs indicate the percentage increase in MAC that attends knockout. The increases vary by nearly an order of magnitude (e.g., 7% for desflurane, 15% for sevoflurane, and 47% for halothane), but do not correlate with the capacity of these anesthetics to enhance the response of the TREK-1 channel in vitro (bottom graph)., The failure of the correlation calls into question the relevance of TREK-1 channels as mediators of the immobility produced by inhaled anesthetics.