Contrasting Roles of the N-Methyl-d-Aspartate Receptor in the Production of Immobilization by Conventional and Aromatic Anesthetics

Abstract

We hypothesized that N-methyl-d-aspartate (NMDA) receptors mediate some or all of the capacity of inhaled anesthetics to prevent movement in the face of noxious stimulation, and that this capacity to prevent movement correlates directly with the in vitro capacity of such anesthetics to block the NMDA receptor. To test this hypothesis, we measured the effect of IV infusion of the NMDA blockers dizocilpine (MK-801) and (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP) to decrease the MAC (the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects given a noxious stimulation) of 8 conventional anesthetics (cyclopropane, desflurane, enflurane, halothane, isoflurane, nitrous oxide, sevoflurane, and xenon) and 8 aromatic compounds (benzene, fluorobenzene, o-difluorobenzene, p-difluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene, pentafluorobenzene, and hexafluorobenzene) and, for comparison, etomidate. We postulated that MK-801 or CPP infusions would decrease MAC in inverse proportion to the in vitro capacity of these anesthetics to block the NMDA receptor. This notion proved correct for the aromatic inhaled anesthetics, but not for the conventional anesthetics. At the greatest infusion of MK-801 (32 microg x kg(-1) x min(-1)) the MACs of conventional anesthetics decreased by 59.4 +/- 3.4% (mean +/- sd) and at 8 microg x kg(-1) x min(-1) by 45.5 +/- 4.2%, a decrease not significantly different from a 51.4 +/- 19.0% decrease produced in the EC50 for etomidate, an anesthetic that acts solely by enhancing gamma-amino butyric acid (GABA) receptors. We conclude that some aromatic anesthetics may produce immobility in the face of noxious stimulation by blocking the action of glutamate on NMDA receptors but that conventional inhaled anesthetics do not.

Isoflurane depression of spinal nociceptive processing and minimum alveolar anesthetic concentration are not attenuated in mice expressing isoflurane resistant γ-aminobutyric acid type-A receptors

“…These studies imply that other targets are the primary mediators of MAC for inhaled anesthetics; these targets include receptors for N-methyl-D-aspartate and glycine, and possibly voltage gated sodium channels [5,6,21]. However, pharmacologic studies are limited by the specificity of the drugs used.…”

Lidocaine, MK-801, and MAC

“…With conventional anesthetics, lidocaine should produce the previously described decrease of 50%-60% in MAC consequent to the infusion of lidocaine for conventional anesthetics but not for o-difluorobenzene which, at MAC, itself (alone) already blocks most NMDA receptors (7). That is, lidocaine infusion should have little effect on the MAC of o-difluorobenzene.…”

“…In humans, MAC decreases approximately 40% [determined as the effect in the presence of 70% nitrous oxide plus morphine premedication (1)]; in dogs the decrease is 37% (2) to 43% (3); in cats, 52% (4); in ponies by up to 70%, (5) and in rats, 50% (6). A maximum decrease of approximately 40%-50% appears to result, at least for some anesthetics and animals (1,6), a value similar to the 50%-60% maximum decrease produced by the blockade of N-methyl-d-aspartate (NMDA) receptors by dizocilpine (MK-801) (7). Is the mechanism underlying the decrease in MAC the same for MK-801 and lidocaine, i.e., blockade of transmission via NMDA receptors?…”

GABA_A Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

“…These agents inhibit NMDA receptors by 60-74% at one minimum alveolar concentration of drug [24] , and the immobilizing potency of these and other substituted benzenes is postulated to depend on NMDA receptor inhibition [25] . However, at these near-saturated concentrations, low-affinity GABA A receptor interactions also occur.…”