Abstract
The prevalence of obstructive sleep apnea (OSA) in Americans is 9% and increasing. Increased afferent vagal activation may predispose to OSA by reducing upper airway muscle activation/patency and disrupting respiratory rhythmogenesis. Vagal afferent neurons are inhibited by cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors in animal models of vagally-mediated behaviors. Injections of dronabinol, a non-selective CB1/CB2 receptor agonist, into the nodose ganglia reduced serotonin (5-HT)-induced reflex apneas. It is unknown what role CB1 and/or CB2 receptors play in reflex apnea. Here, to determine the independent and combined effects of activating CB1 and/or CB2 receptors on dronabinol’s attenuating effect, rats were pre-treated with CB1 (AM251) and/or CB2 (AM630) receptor antagonists. Adult male Sprague-Dawley rats were anesthetized, instrumented with bilateral electrodes to monitor genioglossus electromyogram (EMGgg) and a piezoelectric strain gauge to monitor respiratory pattern. Following intraperitoneal treatment with AM251 and/or AM630, or with vehicle, serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, the nodose ganglia were exposed and 5-HT-induced reflex apneas were again recorded to confirm that the nerves remained functionally intact. Dronabinol was injected into each nodose ganglion and 5-HT infusion was repeated. Prior to dronabinol injection, there were no significant differences in 5-HT-induced reflex apneas or phasic and tonic EMGgg before or after surgery in the CB1, CB2, combined CB1/CB2 antagonist, and vehicle groups. In the vehicle group, dronabinol injections reduced 5-HT-induced reflex apnea duration. In contrast, dronabinol injections into nodose ganglia of the CB1, CB2, and combined CB1/CB2 groups did not attenuate 5-HT-induced reflex apnea duration. However, the CB1 and CB2 antagonists had no effect on dronabinol’s ability to increase phasic EMGgg. These findings underscore the therapeutic potential of dronabinol in the treatment of OSA and implicate participation of both cannabinoid receptors in dronabinol’s apnea suppression effect.
Highlights
Sleep-disordered breathing (SDB) is characterized by repeated apnea and hypopnea events [1]
SDB contributes to acute pathophysiological consequences, such as hypoxemia/hypercapnia, fragmented sleep, and exaggerated fluctuations in heart rhythm, blood pressure, and intrathoracic pressure, that can develop into long-term sequelae such as hypertension and other cardiovascular morbidities [1,2,3]
But there are no approved pharmacologic treatments for obstructive sleep apnea (OSA) [5], and efforts to develop such treatments have been hampered by incomplete knowledge of the relevant state-dependent peripheral and central neural mechanisms controlling upper airway muscles
Summary
Sleep-disordered breathing (SDB) is characterized by repeated apnea and hypopnea events [1]. SDB contributes to acute pathophysiological consequences, such as hypoxemia/hypercapnia, fragmented sleep, and exaggerated fluctuations in heart rhythm, blood pressure, and intrathoracic pressure, that can develop into long-term sequelae such as hypertension and other cardiovascular morbidities [1,2,3]. The most prevalent SDB, affecting 14% and 5% of American men and women, respectively, is obstructive sleep apnea (OSA) [1]. Standard treatment for OSA is to pneumatically splint the upper airway using continuous positive airway pressure (CPAP). But there are no approved pharmacologic treatments for OSA [5], and efforts to develop such treatments have been hampered by incomplete knowledge of the relevant state-dependent peripheral and central neural mechanisms controlling upper airway muscles
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