The hypocretin (orexin) system: from a neural circuitry perspective

BACKGROUND
A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia.

Activation of D1 Dopamine Receptors Induces Emergence from Isoflurane General Anesthesia

The emergence from anesthesia is the stage of general anesthesia featuring the patient's progression from the unconsciousness status to wakefulness and restoration of consciousness. This complex process has precise neurobiology which differs from that of induction. Despite the medications commonly used in anesthesia allow recovery in a few minutes, a delay in waking up from anesthesia, called delayed emergence, may occur. This phenomenon is associated with delays in the operating room, and an overall increase in costs. Together with the emergence delirium, the phenomenon represents a manifestation of inadequate emergence. Nevertheless, in delayed emergence, the transition from unconsciousness to complete wakefulness usually occurs along a normal trajectory, although slowed down. On the other hand, this awakening trajectory could proceed abnormally, possibly culminating in the manifestation of emergence delirium. Clinically, delayed emergence often represents a challenge for clinicians who must make an accurate diagnosis of the underlying cause to quickly establish appropriate therapy. This paper aimed at presenting an update on the phenomenon, analyzing its causes. Diagnostic and therapeutic strategies are addressed. Finally, therapeutic perspectives on the "active awakening" are reported.

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Delayed Emergence from Anesthesia: What We Know and How We Act

Background Orexin can facilitate emergence after general anaesthesia via multiple neural pathways. Dopaminergic neurones in the ventral tegmental area (VTA) participate in behavioural arousal from anaesthesia. We investigated the regulation of dopaminergic VTA neurones by orexinergic neurones during emergence from general anaesthesia. Methods Orexins were microinjected into the VTA to determine the effects on isoflurane anaesthesia induction, emergence, and maintenance. Orexin receptors and dopaminergic neurones in the VTA were identified using immunofluorescence. Orexinergic terminals in the VTA were optogenetically regulated to detect the endogenous orexin-mediated regulation of dopaminergic neurones during anaesthesia in Hcrtcre rats. Results Injection of orexin-A (100 pmol) into the VTA reduced emergence time [from 949 (118) to 727 (101) s; P=0.0058] and reduced the electroencephalographic burst–suppression ratio (BSR) (26.6 [10.2]% vs 44.3 [6.8]%; P=0.0027) during isoflurane anaesthesia. The percentage of dopaminergic neurones that expressed either orexin-1 receptor or orexin-2 receptor was 73.4 (5.0)% and 74.4 (62.4)%, respectively. Optogenetic activation of orexinergic projections to the VTA reduced the BSR (from 40.5 [2.7]% to 22.4 [11.8]%; P=0.0019) and facilitated emergence (915 [89] vs 685 [68] s; P=0.0026), whereas optical inhibition prolonged the time to wakefulness (from 941 [92] to 1279 [250] s; P=0.011). Dopaminergic neurones in the VTA showed increased firing frequency (387 [78]% of control, P=0.005) after bath application of orexin-A. Conclusions Orexin promotes emergence from isoflurane anaesthesia through activation of dopaminergic neurones in the VTA.

Orexin activated emergence from isoflurane anaesthesia involves excitation of ventral tegmental area dopaminergic neurones in rats.

Nucleus accumbens neurons expressing dopamine D1 receptors modulate states of consciousness in sevoflurane anesthesia

Background The neuropeptide orexin promotes arousal from general anaesthesia, however the neuronal circuits that mediate this effect have not been defined. We investigated whether orexinergic neurones modulate the basal forebrain (BF) and locus coeruleus (LC) in emergence from anaesthesia. Methods Hcrtcre rats were generated using a CRISPR/Cas9-based approach. Viruses encoding optogenetic probes were injected into the perifornical lateral hypothalamic (PeFLH) area, optogenetic fibres were embedded in the PeFLH, BF, or LC, and changes in anaesthesia state under 1.4 vol% or 0.8 vol% isoflurane were determined. Results In the PeFLH, 98.8% (0.4%) of orexin-A-positive cells expressed tdTomato, and 91.9% (2.2%) of tdTomato cells were orexin-A-positive. Under 1.4 vol% isoflurane anaesthesia, compared with control groups, burst suppression ratio was less, and emergence time was shorter in groups with optogenetic activation of orexinergic cell bodies in the PeFLH (923 [162] vs 493 [68] s, P=0.0003) or orexinergic terminals in the BF (937 (122) vs 674 (108) s, P=0.0049) or LC (913 [128] vs 742 [76] s, P=0.022). Optical stimulation of orexinergic terminals in the BF and LC also improved the movement scores of rats under 0.8 vol% isoflurane anaesthesia. Conclusions Activation of orexinergic terminals in the FB or LC mediates facilitation of emergence from anaesthesia by orexinergic neurones during isoflurane anaesthesia.

Selective optogenetic activation of orexinergic terminals in the basal forebrain and locus coeruleus promotes emergence from isoflurane anaesthesia in rats.

Serotonergic neurons in the dorsal raphe nucleus mediate the arousal-promoting effect of orexin during isoflurane anesthesia in male rats

In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity-dependent tagging revealed a subset of ventral tegmental area γ-aminobutyric acid (GABA)–somatostatin (VTAVgat-Sst) cells that sense stress and drive non–rapid eye movement (NREM) and REM sleep through the lateral hypothalamus and also inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTAVgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTAVgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone concentrations remained increased after stress. Thus, a specific circuit allows animals to restore mental and body functions by sleeping, potentially providing a refined route for treating anxiety disorders. Description Sleep as a response to stress Stress-induced sleep has been hypothesized to dampen stress responses and to help mental processing of the stressful events. However, the mechanisms underlying these phenomena are not understood. Yu et al. discovered a specific circuit in the mouse midbrain dedicated to detecting stress and inducing restorative sleep (see the Perspective by Joëls and de Kloet). A subset of specialized neurons receive stress inputs and induce rapid eye movement (REM) and non-REM sleep through the lateral hypothalamus. Transient stress enhanced the activity of these neurons for several hours. Stress-induced sleep generated by this pathway alleviated stress levels and mitigated stress-induced anxiety, restoring mental and body functions. Sleep after stress can thus profoundly reduce the chronic stress response. —PRS In mice, social defeat stress has sleep-enhancing effects that protect against continuing stress and anxiety.

A specific circuit in the midbrain detects stress and induces restorative sleep

Background Orexin, a neuropeptide derived from the perifornical area of the hypothalamus (PeFLH), promotes the recovery of propofol, isoflurane, and sevoflurane anesthesias, without influencing the induction time. However, whether the orexinergic system also plays a similar role in desflurane anesthesia, which is widely applied in clinical practice owing to its most rapid onset and offset time among all volatile anesthetics, has not yet been studied. In the present study, we explored the effect of the orexinergic system on the consciousness state induced by desflurane anesthesia. Methods The c-Fos staining was used to observe the activity changes of orexinergic neurons in the PeFLH and their efferent projection regions under desflurane anesthesia. Chemogenetic and optogenetic techniques were applied to compare the effect of PeFLH orexinergic neurons on the induction, emergence, and maintenance states between desflurane and isoflurane anesthesias. Orexinergic terminals in the paraventricular thalamic nucleus (PVT) were manipulated with pharmacologic, chemogenetic, and optogenetic techniques to assess the effect of orexinergic circuitry on desflurane anesthesia. Results Desflurane anesthesia inhibited the activity of orexinergic neurons in the PeFLH, as well as the neuronal activity in PVT, basal forebrain, dorsal raphe nucleus, and ventral tegmental area, as demonstrated by c-Fos staining. Activation of PeFLH orexinergic neurons prolonged the induction time and accelerated emergence from desflurane anesthesia but only influenced the emergence in isoflurane anesthesia, as demonstrated by chemogenetic and pharmacologic techniques. Meanwhile, optical activation of orexinergic neurons exhibited a long-lasting inhibitory effect on burst-suppression ratio (BSR) under desflurane anesthesia, and the effect may be contributed by the orexinergic PeFLH-PVT circuitry. The orexin-2 receptor (OX2R), but not orexin-1 receptor (OX1R), in the PVT, which had been inhibited most significantly by desflurane, mediated the proemergence effect of desflurane anesthesia. Conclusions We discovered, for the first time, that orexinergic neurons in the PeFLH could not only influence the maintenance and emergence from isoflurane and desflurane anesthesias but also affect the induction under desflurane anesthesia. Furthermore, this specific effect is probably mediated by orexinergic PeFLH-PVT circuitry, especially OX2Rs in the PVT.

Activation of Orexinergic Neurons Inhibits the Anesthetic Effect of Desflurane on Consciousness State via Paraventricular Thalamic Nucleus in Rats.

Sleep deprivation (SD) especially insomnia is commonly encountered in clinic. Many factors can cause insomnia, such as anxiety, fear, pain, medication, and disruptive environment [1]. Sleep disorder during the perioperative period may cause a number of complications, including delayed anesthesia emergence. However, the mechanism underlying this phenomenon remains elusive. It has been postulated that common neural pathways between natural sleep and general anesthesia may be involved in the regulation of anesthesia emergence times [2]. Orexin is a peptide that consists of orexin-A (OXA) and orexin-B (OXB) subtypes [3]. Accumulated evidence suggests that orexinergic neurons play a critical role in the promotion and maintenance of wakefulness [4]. It has been reported that orexinergic neurons participate in the control of rapid eye movement (REM) sleep and the orexin-1 receptor is particularly necessary in the suppression of REM sleep [5]. Our earlier studies demonstrated that activation of the orexinergic signals in the basal forebrain significantly increased acetylcholine efflux in the somatosensory cortical region and shortened the awakening time of rats under inhalation or intravenous anesthesia [6]. These findings strongly supported the notion that orexinergic neurons might play a crucial role in the regulation of postanesthesia arousal. It has been reported that the anesthesia behaviors of rats change after SD in terms of time of reduced loss of righting reflex (LORR) and delayed recovery of the righting reflex (RORR) [7]. These alterations strongly suggest that sleep pattern changes might modulate the effectiveness of general anesthetics. Furthermore, administration of adenosine A1 and A2 receptor antagonists partially reversed the effect of SD, but the awakening time did not return to its original length [8]. We hypothesize that the delayed emergence from general anesthesia after SD is associated with the orexinergic neural pathway and experimentally verified the hypothesis in the rat. To determine whether the delayed emergence from anesthesia after SD is due to the alteration of the orexinergic neuron’s activity, the animals were divided into two groups: SD group and sham-SD group. We adopted a modified multiple-platform method to deprive REM sleep of the rats in SD group for 24 h. The plasma OXA concentrations were measured by radioimmunoassay (RIA) after SD. Results showed that the plasmic concentration of OXA in the sham-SD group was 25.2 2.43 pg/mL, but decreased to 17.8 1.29 pg/mL at 24 h after sleep deprivation. Next, we recorded both induction and emergence time in the two groups of rats subjected to isoflurane anesthesia. We found that the SD had no effects on the induction time, but increased the duration of emergence in isoflurane anesthesia. The induction time of the SD group (1.90 0.12 min) was similar to that of the sham-SD group (1.83 0.09 min, P < 0.05). However, the emergence time in the SD rats (16.9 0.63 min) was significantly longer than that of the sham-SD group (14.8 0.42 min; P < 0.05). The brain sections were double immunofluorescently stained for orexin and c-Fos in hypothalamic neurons to determine the orexinergic neuron’s activity. The orexinergic neuron activity was observed at four time points: before and after the sleep deprivation, 30 min of isoflurane anesthesia, and at emergence. Approximately 140–170 orexin-positive neurons were detected in each section. Of them, the percentage of OXA and c-Fos double-labeled neurons was 45.4 6.5% before SD. After 24 h SD, the total number of OXA-positive neurons did not change

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12380

Jiannan Li

Papers

Selective optogenetic activation of orexinergic terminals in the basal forebrain and locus coeruleus promotes emergence from isoflurane anaesthesia in rats.

Serotonergic neurons in the dorsal raphe nucleus mediate the arousal-promoting effect of orexin during isoflurane anesthesia in male rats

A specific circuit in the midbrain detects stress and induces restorative sleep

Activation of Orexinergic Neurons Inhibits the Anesthetic Effect of Desflurane on Consciousness State via Paraventricular Thalamic Nucleus in Rats.

Reduction of orexin-A is responsible for prolonged emergence of the rat subjected to sleep deprivation from isoflurane anesthesia.