Abstract
BackgroundEvidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Here, we examine the effects of intracerebroventricular (ICV) injection of dronabinol on serotonin (5-HT)-induced apnea.MethodsAdult male Sprague-Dawley rats were anesthetized and instrumented with bilateral electrodes to monitor genioglossi EMG and with a piezoelectric strain gauge to monitor respiratory pattern. Serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, rats were placed in a stereotaxic apparatus. A unilateral osteotomy was made to allow access for injection to the right lateral ventricle, and the dura were carefully removed. Dronabinol (100, 10, 1, or 0.1 μg/3 μl DMSO) or control (3 μl DMSO) was injected into the right lateral ventricle and 5-HT infusion was repeated. Data (mean ± SEM) were analyzed using a mixed model analysis with a repeated/fixed measure.ResultsThere was no main effect in 5-HT-induced apnea or breath duration, or in breath instability, between ICV dronabinol injected and ICV vehicle control injected groups. Moreover, there was no main effect in phasic or tonic genioglossus activity between ICV dronabinol injected and ICV vehicle control injected groups.ConclusionOur data show that ICV injection of dronabinol did not decrease 5-HT-induced apneas, and did not increase genioglossus activity. This in contrast to published results of dronabinol’s effect on apnea via the vagus nerve. Our results suggest that the effects of dronabinol on reflex apneas are peripherally mediated via suppression of vagal nerve activity.
Highlights
Evidence suggests that vagal nerve activity may play a role in sleep apnea induction
Though we have shown previously that modulation of vagal afferents via activation of CB receptors located on nodose ganglion neurons can attenuate reflex apneas [14, 15], it was uncertain what role central CB receptors play in respiratory pattern control
In conclusion, we show that ICV injections of dronabinol, a non-specific CB agonist, had no effect on 5-HTinduced reflex apnea, and had no effect on genioglossus activity
Summary
Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. Dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. It is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Obstructive sleep apnea (OSA), characterized by a cessation of breathing produced by a narrowed or collapsed upper airway, represents a significant public health risk [1, 2]. Activating the inhibitory Gi/o-associated cannabinoid (CB) receptors have been proposed as novel pharmacological intervention to treat OSA [7, 8]
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