Increased NMDA receptor inhibition at an increased Sevoflurane MAC

Abstract

Background: Sevoflurane potently enhances glycine receptor currents and more modestly decreases NMDA receptor currents, each of which may contribute to immobility. This modest NMDA receptor antagonism by sevoflurane at a minimum alveolar concentration (MAC) could be reciprocally related to large potentiation of other inhibitory ion channels. If so, then reduced glycine receptor potency should increase NMDA receptor antagonism by sevoflurane at MAC.

Methods: Indwelling lumbar subarachnoid catheters were surgically placed in 14 anesthetized rats. Rats were anesthetized with sevoflurane the next day, and a pre-infusion sevoflurane MAC was measured in duplicate using a tail clamp method. Artificial CSF (aCSF) containing either 0 or 4 mg/mL strychnine was then infused intrathecally at 4 μL/min, and the post-infusion baseline sevoflurane MAC was measured. Finally, aCSF containing strychnine (either 0 or 4 mg/mL) plus 0.4 mg/mL dizocilpine (MK-801) was administered intrathecally at 4 μL/min, and the post-dizocilpine sevoflurane MAC was measured.

Results: Pre-infusion sevoflurane MAC was 2.26%. Intrathecal aCSF alone did not affect MAC, but intrathecal strychnine significantly increased sevoflurane requirement. Addition of dizocilpine significantly decreased MAC in all rats, but this decrease was two times larger in rats without intrathecal strychnine compared to rats with intrathecal strychnine, a statistically significant (P < 0.005) difference that is consistent with increased NMDA receptor antagonism by sevoflurane in rats receiving strychnine.

Conclusions: Glycine receptor antagonism increases NMDA receptor antagonism by sevoflurane at MAC. The magnitude of anesthetic effects on a given ion channel may therefore depend on the magnitude of its effects on other receptors that modulate neuronal excitability.

Figure 1

Sevoflurane MAC before and after intrathecal administration of CO₂-acidified aCSF either without (control) or with 4 mg/mL strychnine. Statistically significant differences are indicated by an asterisk (*). MAC was unchanged in control animals, indicating that neither intrathecal administration of aCSF nor CO₂ significantly altered sevoflurane requirement. In contrast, intrathecal strychnine significantly increased sevoflurane MAC.

Figure 2

Sevoflurane MAC during intrathecal administration of CO₂-acidified aCSF (MAC-aCSF) and during administration of acidified aCSF containing 0.4 mg/mL dizocilpine (MAC-dizocilpine), either without (control) or with 4 mg/mL strychnine. The strychnine MAC values were both significantly greater than their corresponding control sevoflurane MAC values (* P < 0.05) The difference in sevoflurane MAC before and after dizocilpine administration is shown in the far right bars for both control (C) and strychnine (S) rats.