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

* Fellow, † Research Assistant, ‡ Medical Student, § Professor, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.
Anesthesiology (Impact Factor: 5.88). 12/2012; 118(2). DOI: 10.1097/ALN.0b013e31827d413e
Source: PubMed


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.

Three sets of experiments used 51 mice. First, breathing was measured by plethysmography after PRF microinjection of the adenosine A1 receptor agonist N-sulfophenyl adenosine (SPA) or saline. Second, mice were anesthetized with isoflurane and the time to recovery of righting response (RoRR) was quantified after a 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, or SPA and 1, 3-dipropyl-8-cyclopentylxanthine.

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%). 1, 3-dipropyl-8-cyclopentylxanthine alone caused a concentration-dependent increase in acetylcholine, a decrease in RoRR, and a decrease in breathing rate. Coadministration of SPA and 1, 3-dipropyl-8-cyclopentylxanthine blocked the SPA-induced decrease in acetylcholine and increase in RoRR.

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.

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    • "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 the 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). "
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    ABSTRACT: Human obesity is associated with increased leptin levels and pain, but the specific brain regions and neurochemical mechanisms underlying this association remain poorly understood. This study used adult male C57BL/6J (B6, n = 14) mice and leptin-deficient, obese B6.Cg-Lep(ob)/J (obese, n = 10) mice to evaluate the hypothesis that nociception is altered by systemic leptin levels and by adenosine A1 receptors in the pontine reticular formation. Nociception was quantified as paw withdrawal latency (PWL) in s after onset of a thermal stimulus. PWL wasconverted topercent maximum possible effect (%MPE). After obtaining baseline PWL measures, the pontine reticular formation was microinjected with saline (control), three concentrations of the adenosine A1 receptor agonist N(6)-p-sulfophenyladenosine (SPA), or super-active mouse leptin receptor antagonist (SMLA) followed by SPA 15 min later, and PWL was again quantified. In obese, leptin-deficient mice, nociception was quantified before and during leptin replacement via subcutaneous osmotic pumps. SPA was administered into the pontine reticular formation of leptin-replaced mice and PWL testing was repeated. During baseline (before vehicle or SPA administration), PWL was significantly (p = 0.0013) lower in leptin-replaced obese mice than in B6 mice. Microinjecting SPA into the pontine reticular formation of B6 mice caused a significant (p = 0.0003) concentration-dependent increase in%MPE. SPA also significantly (p < 0.05) increased%MPE in B6 mice and in leptin-replaced obese mice, but not in leptin-deficient obese mice. Microinjection of the mouse super-active leptin antagonist (SMLA) into the pontine reticular formation before SPA did not alter PWL. The results show for the first time that pontine reticular formation administration of the adenosine A1 receptor agonist SPA produced antinociception only in the presence of systemic leptin. The concentration-response data support the interpretation that adenosine A1 receptors localized to the pontine reticular formation significantly alter nociception.
    Neuroscience 06/2014; 275. DOI:10.1016/j.neuroscience.2014.06.025 · 3.36 Impact Factor

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