Neuronal mechanisms of adenosine A_2A receptors in the loss of consciousness induced by propofol general anesthesia with functional magnetic resonance imaging

Abstract

Propofol is the most common intravenous anesthetic agent for induction and maintenance of anesthesia, and has been used clinically for more than 30 years. However, the mechanism by which propofol induces loss of consciousness (LOC) remains largely unknown. The adenosine A2A receptor (A2AR) has been extensively proven to have an effect on physiological sleep. It is, therefore, important to investigate the role of A2AR in the induction of LOC using propofol. In the present study, the administration of the highly selective A2AR agonist (CGS21680) and antagonist (SCH58261) was utilized to investigate the function of A2AR under general anesthesia induced by propofol by means of animal behavior studies, resting‐state magnetic resonance imaging and c‐Fos immunofluorescence staining approaches. Our results show that CGS21680 significantly prolonged the duration of LOC induced by propofol, increased the c‐Fos expression in nucleus accumbens (NAc) and suppressed the functional connectivity of NAc‐dorsal raphe nucleus (DR) and NAc‐cingulate cortex (CG). However, SCH58261 significantly shortened the duration of LOC induced by propofol, decreased the c‐Fos expression in NAc, increased the c‐Fos expression in DR, and elevated the functional connectivity of NAc‐DR and NAc‐CG. Collectively, our findings demonstrate the important roles played by A2AR in the LOC induced by propofol and suggest that the neural circuit between NAc‐DR maybe controlled by A2AR in the mechanism of anesthesia induced by propofol.

<p>Delayed Emergence from Anesthesia: What We Know and How We Act</p>

“…Recent studies suggest that induction and awakening are asymmetric processes. [4][5][6][7] In fact, the neural circuits that mediate induction do not completely overlap those that mediate the AE. The better understanding of these two processes has allowed researchers to start new studies focused on the actively induced transition from unconsciousness to awakening.…”

“…The ending stage of GA characterized by the progression from the patient's unconsciousness status to complete wakefulness and restoration of consciousness (RoC) has precise neurobiology which largely differs from that of the induction phase. [5][6][7] In practical terms, knowledge of the impact of pharmacological factors such as general anesthetics, neuromuscular blocking agents (NMBAs), opioids, or non-pharmacological conditions such as hydroelectrolytic alterations, hypothermia, on AE processes could help in understanding, preventing, and managing the multiple complications that can occur at this stage.…”

Role of adenosine A2A receptors in the loss of consciousness induced by propofol anesthesia

“…On the basis of our previous study (Chen, Li, et al, 2021), we selected the following experimental drug dosages and divided the mice into three groups: Ctr group, CGS group (2.5 mg/kg), and SCH group (6 mg/kg). First, the A 2A R agonist CGS21680 (Selleckchem, cat.…”

“…This study involved no preregistration, no inclusion or exclusion criteria, no sample size calculation, and no test for outliers. The sample size was at least five per group for measuring the adenosine signal and the neuronal activity of GABAergic neurons (Chen et al, 2020), four per group for c ‐Fos staining (Chen, Li, et al, 2021), eight per group for measuring the time of LORR and RORR (Cunha, 2016), and at least five per group for in vivo electrophysiological recordings (Zhao et al, 2021). Mice with the wrong virus injection site or wrong electrodes and cannula implantation site were excluded after verification.…”

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System

“…The adenosine A2A receptor (A2AR) in the NAc and the tuberomammillary nucleus has been reported to regulate physiological sleep [ 67 , 68 ]. Systematic injection of a selective A2AR agonist significantly prolonged the duration of propofol-induced unconsciousness, accompanied by increased c-fos expression in the NAc [ 69 ]. However, the mechanism by which the A2AR agonist prolonged propofol-induced unconsciousness remains unclear.…”