Activation of orexin system facilitates anesthesia emergence and pain control

Abstract

Orexin (also known as hypocretin) neurons in the hypothalamus play an essential role in sleep–wake control, feeding, reward, and energy homeostasis. The likelihood of anesthesia and sleep sharing common pathways notwithstanding, it is important to understand the processes underlying emergence from anesthesia. In this study, we investigated the role of the orexin system in anesthesia emergence, by specifically activating orexin neurons utilizing the designer receptors exclusively activated by designer drugs (DREADD) chemogenetic approach. With injection of adeno-associated virus into the orexin-Cre transgenic mouse brain, we expressed the DREADD receptor hM3Dq specifically in orexin neurons and applied the hM3Dq ligand clozapine to activate orexin neurons. We monitored orexin neuronal activities by c-Fos staining and whole-cell patch-clamp recording and examined the consequence of orexin neuronal activation via EEG recording. Our results revealed that the orexin–DREADD mice with activated orexin neurons emerged from anesthesia with significantly shorter latency than the control mice. As an indication of reduced pain sensitivity, these orexin–DREADD mice took longer to respond to the 55 °C thermal stimuli in the hot plate test and exhibited significantly less frequent licking of the formalin-injected paw in the formalin test. Our study suggests that approaches to activate the orexin system can be beneficial in postoperative recovery.

Optogenetic/Chemogenetic Activation of GABAergic Neurons in the Ventral Tegmental Area Facilitates General Anesthesia via Projections to the Lateral Hypothalamus in Mice

“…Evidence shows that both isoflurane and sevoflurane inhibit wake-active orexinergic neurons (Kelz et al, 2008). Zhou et al (2018) showed that chemogenetic activation of orexinergic neurons in the hypothalamus shortened emergence time from anesthesia (Zhou et al, 2018). These studies support a crucial role for LH orexinergic neurons in emergence from anesthesia; they also indicate that VTA GABA-LH projections regulating anesthesia and arousal may at least partially target orexinergic neurons.…”

“…With a great deal of axonal innervation from the VTA, the LH has been reported to regulate arousal, energy homeostasis, feeding behavior, and reward processing. Moreover, orexin (hypocretin) neurons in the LH play a vital role in the promotion and maintenance of wakefulness, both in general anesthesia and in sleep (Dong et al, 2006; Zhang et al, 2012; Cun et al, 2014; Zhou et al, 2018). Our previous studies have suggested that excitation of LH orexinergic neurons could facilitate emergence from propofol and isoflurane anesthesia via modulation of basal forebrain (BF) activity (Zhang et al, 2012, 2016).…”

Regulation of perceptual learning by chronic chemogenetic manipulation of parvalbumin-positive interneurons

“…Indeed, the effects of CNO treatment in DREADD-transfected subjects are the result of systemic conversion to clozapine (Gomez et al, 2017), which at low -≥ú≤ CNO doses (1 mg/kg) binds almost exclusively to DREADDs and has no known electrophysiological or behavioral effects (MacLaren et al, 2016). These reasons support the increasing use of vehicle treatment instead of CNO in control subjects (e.g., (Farzi et al, 2018;Zhou et al, 2018), the approach we chose for the present study.…”

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

“…Genetic and pharmacological ablation of orexinergic signaling delays recovery of consciousness after general anesthesia in mice, although the anesthetic dose requirement for inducing unconsciousness is unchanged [64]. Accordingly, chemogenetic activation of orexin neurons promotes emergence from isoflurane anesthesia in mice [123]. These reports suggest that orexinergic neurons are important for anesthetic emergence, but not induction.…”