Cannabinoid Type 1 and Type 2 Receptor Antagonists Prevent Attenuation of Serotonin-Induced Reflex Apneas by Dronabinol in Sprague-Dawley Rats

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.

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review

“…Thus, less than 20 years ago, the system of endogenous cannabinoids or endocannabinoids was discovered. Since then, the impact of that system at physiological and behavioural level has been studied constantly [21][22][23][24][25][26][27].…”

Intracerebroventricular injections of dronabinol, a cannabinoid receptor agonist, does not attenuate serotonin-induced apnea in Sprague-Dawley rats

“…Dronabinol, when administered to patients with OSA [ 12 ], or to rats chronically-instrumented to measure respiration during sleep [ 13 ], decreased apneas. The mechanism of dronabinol’s effect in decreasing apnea propensity appeared to be, in part, due to the activation of both CB 1 and CB 2 receptors located on nodose ganglia of the vagus nerves [ 14 , 15 ], which transmit vital information from the lungs to the brainstem, contributing to reflex responses regulating: tidal volume, respiratory frequency, augmented breaths and bronchoconstriction [ 16 , 17 ]. In a well-established model of vagally-mediated reflex apnea [ 18 ], dronabinol injected into nodose ganglia attenuated apneas [ 15 ].…”

DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep

“…The simplest explanation for this effect was that the increased concentration of DMSO increased the absorption and bioavailability of dronabinol [3]. Increased absorption and bioavailability of dronabinol could increase activation of CB receptors on the nodose ganglia, which play a part in apnea suppression [19,20]. However, we cannot rule out that DMSO potentiated the effects of dronabinol, by either modulating vagal nerve activity [9,27], or by modulating pulmonary ventilation [12], or both.…”

“…Dronabinol, a synthetic version of Δ 9-THC, is a lipophilic substance that has been previously used to suppress apneas in preclinical studies [17,18] by a mechanism that involves modulation of vagus nerve activity via CB receptors on nodose ganglia [19,20]. In those preclinical studies, dronabinol was dissolved in undiluted DMSO since DMSO was known to increase bioavailability of the lipophilic drugs [3][4][5].…”

“…Administration of dronabinol, a synthetic cannabinoid type 1 (CB 1 ) and cannabinoid type 2 (CB 2 ) receptor agonist, dissolved in undiluted DMSO (1ml) decreased apnea index and rapid eye movement (REM) sleep in rats [17,18]. Recent experiments using a model of reflex apnea in anesthetized rats implicates the activation of cannabinoid (CB) receptors on the nodose ganglia in the apnea-suppressive effect [19,20], with little impact deriving from CB receptors located in the brain [21].…”