Microtubule-Stabilizer Epothilone B Delays Anesthetic-Induced Unconsciousness in Rats

Abstract

Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of microtubule-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant microtubule-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 seconds longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen’s d) of 1.9, indicating a “large” normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to microtubules causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural microtubules.Significance statementOur study establishes that action on intracellular microtubules is the mechanism, or one of the mechanisms, by which the inhalational anesthetic gas isoflurane induces unconsciousness in rats. This finding has potential clinical implications for understanding how taxane chemotherapy interferes with anesthesia in humans, and more broadly for avoiding anesthesia failures during surgery. Our results are also theoretically important because they provide support for microtubule-based theories of anesthetic action and consciousness.