Revisiting MAC as a static measure of anaesthesia: evidence for dynamic responses under isoflurane in male mice

Background The presence of a righting reflex is known to vary over time in an individual at the population half-maximal effective anaesthetic concentration (EC 50 ). However, it is unclear whether similar variability occurs for other anaesthetic endpoints at comparable anaesthetic concentrations. We sought to test whether individual responses to a pedal pinch, a strong aversive stimulus, vary over time in individuals at the population EC 50 for stimulus response and to explore the dynamics of individual responses. Methods Male mice were exposed to fixed concentrations of isoflurane, and aversive pedal stimulation was repeatedly assessed to determine a population EC 50 . In a second cohort of male mice, either righting reflex or pedal pinch was repeatedly assessed at empirically determined population EC 50 values for those stimuli (0.6 vol% and 0.95 vol%, respectively) over multiple anaesthetic exposures. Stochasticity of responses was determined by evaluating if response dwell times correspond to exponential distributions. The presence of resistance to state transitions (RST) in responses was tested by simulation of response data using a process lacking any RST, comparing real data with the simulated data. Results Like a righting reflex, at a population EC 50 for response to an aversive stimulus, individual mice switch between responsive and unresponsive states. These responses are stochastic and display resistance to state transitions. Neither individual sensitivity nor RST for righting reflex at population EC 50 (0.6 vol% isoflurane) was predictive of sensitivity or RST for aversive stimulus response at its population EC 50 (0.95 vol% isoflurane). Conclusions Similar to the righting reflex, responses to an aversive stimulus change stochastically in individuals at population EC 50 but differ from the dynamics seen with a righting reflex such that sensitivity and resistance to state transition are dependent on the test and vary independently between test modalities within an individual.