Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents

Abstract

How general anesthetics work remains a topic of ongoing study. A parallel field of research has sought to identify methods to reverse general anesthesia. Reversal agents could shorten patients' recovery time and potentially reduce the risk of postoperative complications. An incomplete understanding of the mechanisms of general anesthesia has hampered the pursuit for reversal agents. Nevertheless, the search for reversal agents has furthered understanding of the mechanisms underlying general anesthesia. The study of potential reversal agents has highlighted the importance of rigorous criteria to assess recovery from general anesthesia in animal models, and has helped identify key arousal systems (e.g., cholinergic, dopaminergic, and orexinergic systems) relevant to emergence from general anesthesia. Furthermore, the effects of reversal agents have been found to be inconsistent across different general anesthetics, revealing differences in mechanisms among these drugs. The presynapse and glia probably also contribute to general anesthesia recovery alongside postsynaptic receptors. The next stage in the search for reversal agents will have to consider alternate mechanisms encompassing the tripartite synapse.

Figure 1:. Potential targets of select reversal agents

Presynaptic targets While many postsynaptic targets of general anesthetics have been explored, there are many presynaptic proteins that have yet to be investigated as potential targets for reversal agents. A variety of presynaptic ion channels (A and B),^– electron transport proteins in mitochondria (C),^, kinesins (D), and SNARE complex proteins (E)^, have all been identified to be general anesthetic targets but none of these proteins have reversal agents targeted to them. However, there are some potential reversal agents which enhance the release of excitatory neurotransmitters.^,, (F) Caffeine can accelerate emergence from general anesthesia in rats possibly by blocking adenosine receptors and elevating intracellular cAMP levels.^, (G) Other reversal agents counter the effects of specific sedatives. Atipamezole antagonizes the α2-adrenergic receptor, a target for the sedative dexmedetomidine. Synapse-associated glia represent another likely arena of general anesthetic target mechanisms, such as neurotransmitter recycling, gap junction communication, and ion channel function (reviewed in ). These are not shown. Postsynaptic targets A myriad of postsynaptic receptors has been targeted by reversal agents. (H) Flumazenil and naphthalene-etomidate antagonize the GABA_A receptor, combatting the effects of general anesthetics which normally potentiate this receptor.^, Reversal agents can also enhance the effects of excitatory neurotransmitters. (I) Physostigmine inhibits acetylcholinesterase thereby increasing the amount of acetylcholine available in the synaptic cleft. (J) Acetylcholine receptors themselves are inhibited by many anesthetics^, and microinjection of acetylcholine agonists such as nicotine directly into the central medial thalamus of rats can hasten reversal of general anesthesia.

Figure 2:. Stimulation of arousal systems in the rodent brain can reverse general anesthesia

The approximate locations of key regions in the rodent brain are colored according to neurotransmitter type and agonists of these systems are shown in the same color. Black arrows indicate sites of injection of agonists. Grey arrows indicate ascending projections. Stimulation of various arousal systems through microinjection of agonists and optogenetics have helped reveal the importance of these systems in the mechanisms of general anesthetics. (A) Microinjection of nicotine into the central medial thalamus reverses sevoflurane anesthesia. (B) Injection of carbachol to the prefrontal prelimbic cortex reverses sevoflurane anesthesia. In contrast, stimulation of the cholinergic stimulation of the parietal cortex did not restore wake like behavior. (C) Injection of norepinephrine into the nucleus basalis of Meynert in the basal forebrain of mice induces microarousal from desflurane but does not induce full reversal. (D) Injection of orexin A or orexin B into the basal forebrain of rats reduces emergence time from sevoflurane.^,