Increased NMDA receptor inhibition at an increased Sevoflurane MAC

Abstract

BackgroundSevoflurane 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.MethodsIndwelling 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.ResultsPre-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.ConclusionsGlycine 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.

In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography

“…56,57 However, preclinical studies have demonstrated that early exposure to general anesthetics, such as ketamine, isoflurane, nitrous oxide, and sevoflurane, induces widespread neuronal apoptosis in many brain regions in rodent models. 5,6,17,21,25,49,50,58,59 in a previous study, 60 we also provided evidence of sevoflurane-induced neurotoxicity and some observations on the temporal features of this effect in neonatal rats. The first report describing neuronal cell damage in nonhuman primates exposed perinatally to anesthetics was published in 2007.…”

“…Studies have shown that sevoflurane activates glycine and GaBa receptors while antagonizing nMda receptors. [17][18][19][20]79 although the underlying mechanisms are largely unknown, increased oxidative stress associated with mitochondrial dysfunction seems to play an important role in anesthetic-induced neurotoxicity. 28,80,81 From our lipidomic analyses, 82 we noted that alterations in mitochondrial membrane morphology and function were particularly significant, suggesting that mitochondria may be the most vulnerable initial target of anesthesiainduced developmental neurotoxicity.…”

“…[17][18][19][20] in a neonatal rat model, a single episode of sevoflurane-induced general anesthesia (2 to 2.5% for 4 to 6 h) leads to widespread neuronal apoptosis in several brain regions and causes long-term behavioral impairments and memory dysfunction. 4,15,[21][22][23] Repeated treatments with sevoflurane during gestation in the rat induced neuronal apoptosis in the brains of offspring.…”

Monitoring (un)consciousness: the implications of a new definition of ‘anaesthesia’

“…Adapted from Rudolph and Antkowiak [19] using their broad definitions of strong/weak activation/ inhibition (with TASK results added from data of Putzke et al [20] and Pandit et al [21,22]. Results taken for sevoflurane and AMPA from [23], NMDA from [24] and HCN1 from [25]. The table is not comprehensive either for channel types or for agents, and agents with novel actions such as dexmedetomidine [26] are not represented.…”

Anesthetic synergy between two n-alkanes

“…Accordingly, administration of the NMDA receptor antagonist dizocilpine causes a greater reduction of isoflurane MAC in rats when administered spinally, next to the anatomic site of action responsible for immobility, than when administered either intracerebroventricularly or intravenously (Stabernack et al 2003). Furthermore, when either GABA A or glycine receptors are antagonized respectively in isoflurane- or sevoflurane-anesthetized rats, there is increased NMDA receptor antagonism by the volatile anesthetic at MAC, suggesting that greater suppression of glutamatergic excitability might compensate for loss of inhibitory channel contributions to immobility (Brosnan 2011; Brosnan & Thiesen 2012). Volatile agents that can no longer potentiate GABA A receptors are nonimmobilizers (Mihic et al 1994).…”