Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Abstract

Significant progress has been made in the 21 st century towards a comprehensive understanding of the mechanisms of action of general anesthetics, coincident with progress in structural biology and molecular, cellular, and systems neuroscience. This review summarizes important new findings that include target identification through structural determination of anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical roles of neuronal networks in anesthetic effects on memory and consciousness. These recent developments provide a comprehensive basis for conceptualizing pharmacologic control of amnesia, unconsciousness, and immobility.

Recovery of Consciousness and Cognition after General Anesthesia in Humans

“…Anesthetized subjects continued to inhale 1.3 age-adjusted MAC isoflurane anesthesia for three hours. Burst suppression, a sign of deep anesthesia, was found to be associated with this concentration of isoflurane in this cohort (Hemmings et al, 2019;Shortal et al, 2019). Blood pressure was targeted to remain within 20% of baseline pre-induction values using a phenylephrine infusion or intermittent boluses of ephedrine, as necessary.…”

“…Isoflurane anesthesia was chosen because of its heterogeneous molecular targets, which affect multiple neural systems, and because its slower offset compared to other anesthetics would allow us to observe differential recovery of function (Hemmings et al, 2019). The three-hour duration of anesthesia was chosen based on clinical data related to recovery of surgical patients, the pharmacokinetics of isoflurane, and practical considerations for volunteers participating in daylong experiments.…”

Topological Analysis of Differential Effects of Ketamine and Propofol Anesthesia on Brain Dynamics

“…While we have made an effort to make choices that are theoretically grounded and data-driven, further mathematical work may provide better insights and further unify the field. Finally, comparing ketamine and propofol anesthesia is somewhat low-hanging fruit in terms of dynamical-systems analysis of the brain: both NMDA and GABA receptors are widely expressed throughout CNS [23] and so altering activity at these receptors is expected to result in wide-scale changes to brain dynamics. Whether these methods are as effective when comparing more subtle differences in brain function, for example comparing clinically relevant states such as depression, OCD, or schizophrenia, remains to be seen.…”

“…Here we characterize brain dynamics by adapting two complementary models capturing the evolution of whole-brain states through time: the first plots a trajectory through a high-dimensional configuration space, while the other discretizes transitions into a Markovian state-transition network.While ketamine and propofol are both classified broadly as anesthetics, and both obliterate consciousness at high doses, it is useful to compare their different pharmacologies and the differences between the states they induce at low-to-moderate doses. By binding to GABA A receptors, propofol triggers widespread inhibition of neuronal activity and even at low doses, induces states of amnesia, sedation, atonia, and at higher doses, full anesthesia [29,23]. In contrast, ketamine acts primarily as an antagonist of glutamaterigic NMDA receptors [29,66], causing widespread, light central nervous system stimulation and a state typically referred to as "dissociative anesthesia" [16,33].…”

Optogenetic activation of afferent pathways in brain slices and modulation of responses by volatile anesthetics

“…The elusiveness of the mechanisms underlying loss and return of consciousness during anesthesia may be attributed partially to non-linear, synergistic actions of anesthetics at the cellular, network, and systems levels 15 . Isoflurane, for example, suppresses activity within select brain regions 16-18 , impairs connectivity between distant brain regions 19-23 , and diminishes synaptic responses in a pathway-specific manner 24,25 .…”