Adenosine A1 Receptors in Mouse Pontine Reticular Formation Depress Breathing, Increase Anesthesia Recovery Time, and Decrease Acetylcholine Release

Abstract

Background Clinical and preclinical data demonstrate the analgesic actions of adenosine. Central administration of adenosine agonists, however, suppresses arousal and breathing by poorly understood mechanisms. This study tested the two-tailed hypothesis that adenosine A1 receptors in the pontine reticular formation (PRF) of C57BL/6J mice modulate breathing, behavioral arousal, and PRF acetylcholine release. Methods Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N6-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and time to recovery of righting response (RoRR) was quantified after PRF microinjection of SPA or saline. Third, acetylcholine release in the PRF was measured before and during microdialysis delivery of SPA, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), or SPA and DPCPX. Results First, SPA significantly decreased respiratory rate (−18%), tidal volume (−12%) and minute ventilation (−16%). Second, SPA concentration accounted for 76% of the variance in RoRR. Third, SPA concentration accounted for a significant amount of the variance in acetylcholine release (52%), RoRR (98%), and breathing rate (86%). DPCPX alone caused a concentration-dependent increase in acetylcholine, decrease in RoRR, and decrease in breathing rate. Coadministration of SPA and DPCPX blocked the SPA-induced decrease in acetylcholine and increase in RoRR. Conclusions Endogenous adenosine acting at adenosine A1 receptors in the PRF modulates breathing, behavioral arousal, and acetylcholine release. The results support the interpretation that an adenosinergic-cholinergic interaction within the PRF comprises one neurochemical mechanism underlying the wakefulness stimulus for breathing.

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…Abbreviations: KE, ketone ester; KEKS, mix of KE and KS in a 1:1 ratio; KEMCT, mix of KE and medium chain triglyceride (MCT) oil in a 1:1 ratio; KS, ketone salt; KSMCT, mix of KS and MCT oil in a 1:1 ratio; SD, standard diet/control; *p < 0.05; ***p < 0.001; ****p < 0.0001 effects of isoflurane in dogs (e.g., EEG has been changed from a sleep pattern to an awake pattern) [30] and caffeine accelerated emergence from isoflurane-evoked anesthesia in humans [52]. Moreover, enhanced activity of A1Rs (e.g., by an A1R agonist N-sulfophenyl adenosine) may cause increase in anesthesia recovery time [53] and isoflurane may activate A1Rs [54]. It has been demonstrated that receptors of adenosine, such as inhibitory A1Rs and excitatory A2ARs are expressed brain areas implicated in the generation of sleep and sleep-like effects, such as ventrolateral/lateral preoptic area and basal forebrain [29].…”

“…3). Moreover, adenosine receptors may also modulate anesthesia recovery time [52,53]. Thus, it is possible that exogenous ketone supplements not only delay the onset of isoflurane-induced anesthesia (immobility) [23] (Fig.…”

“…Consequently, we propose that the adenosinergic system may be one of main neurotransmitter systems by which ketone supplements can exert their influence on isoflurane-induced anesthesia. However, to get comprehensive view on influence of ketone supplements on isoflurane-evoked anesthesia more studies are needed on other animal strains and humans, on changes not only in adenosinergic, but also other neuromodulatory/ neurotransmitter systems (such as cholinergic, dopaminergic, and GABAergic system), and on other phases of anesthesia/ emergence from anesthesia [24,53,72] by administration of different/higher doses and types of ketone supplements. Further studies are also needed to reveal exact effects of different doses of drugs were used, such as DPCPX and SCH 58261, on isoflurane-generated anesthesia by administration of distinct methods (e.g., not only i.p., but also microinjections/microdialysis to specific brain areas, such as basal forebrain, as well as intravenous administration) [57,58,73].…”

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…Moreover, adenosine accumulates under, for example, sleep deprivation and may have a role in the anesthetic action of isoflurane [28,44]: theophylline (a non-selective antagonist of adenosine receptors) reversed the cerebral effects of isoflurane in dogs (e.g., EEG has been changed from a sleep pattern to an awake pattern) [30] and caffeine accelerated emergence from isoflurane-evoked anesthesia in humans [52]. Moreover, enhanced activity of A1Rs (e.g., by an A1R agonist N-sulfophenyl adenosine) may cause increase in anesthesia recovery time [53] and isoflurane may activate A1Rs [54]. It has been demonstrated that receptors of adenosine, such as inhibitory A1Rs and excitatory A2ARs are expressed brain areas implicated in the generation of sleep and sleep-like effects, such as ventrolateral/lateral preoptic area and basal forebrain [29].…”

Adenosine A1 receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin

“…There is an association between adenosinergic modulation of sleep, obesity-induced sleep disruption, and the impact of sleep quality and duration on the experience of pain. The present study focused on the pontine brain stem because adenosinergic transmission in the pontine reticular formation contributes to the regulation of sleep (Baghdoyan and Lydic, 2012, Gettys et al, 2013) and nociception (Kshatri et al, 1998, Tanase et al, 2002, Wang et al, 2009, Watson et al, 2010). Chronic sleep restriction facilitates development of obesity (Spiegel et al, 1999, Morselli et al, 2010), increases leptin as a modulator of pro-inflammatory cytokines (reviewed in (Hayes et al, 2011), and — even in healthy volunteers — increases pain (Roehrs et al, 2006, Haack et al, 2007).…”