Functional role for cannabinoids in respiratory stability during sleep

Abstract

Study objectives: Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea.

Design: Sleep architecture, respiratory pattern, and apnea expression in rats were assessed by polysomnography. A repeated measures, within-subjects, fully nested crossover design was used in which each animal was recorded on exactly 12 occasions.

Participants: Eleven adult male Sprague-Dawley rats were instrumented for chronic polysomnography.

Interventions: Animals were recorded following intraperitoneal injection of various doses of delta9THC, oleamide, and serotonin, alone and in combination.

Measurements and results: Our data show that delta9THC and oleamide each stabilized respiration during all sleep stages. With delta9THC, apnea index decreased by 42% (F=2.63; p=0.04) and 58% (F=2.68; p=0.04) in NREM and REM sleep, respectively. Oleamide produced equivalent apnea suppression. This observation suggests an important role for endocannabinoids in maintaining autonomic stability during sleep. Oleamide and delta9THC blocked serotonin-induced exacerbation of sleep apnea (p<0.05 for each), suggesting that inhibitory coupling between cannabinoids and serotonin receptors in the peripheral nervous system may act on apnea expression.

Conclusions: This study demonstrates potent suppression of sleep-related apnea by both exogenous and endogenous cannabinoids. These findings are of relevance to the pathogenesis and pharmacological treatment of sleep-related breathing disorders.