Calik Michael W, Carley David W
Center for Narcolepsy, Sleep and Health Research, University of Illinois at Chicago, Chicago, IL.
Department of Biobehavioral Health Science, University of Illinois at Chicago, Chicago, IL.
Sleep. 2017 Sep 1;40(9). doi: 10.1093/sleep/zsx112.
There are no pharmacological treatments for obstructive sleep apnea syndrome, but dronabinol showed promise in a small pilot study. In anesthetized rats, dronabinol attenuates reflex apnea via activation of cannabinoid (CB) receptors located on vagal afferents; an effect blocked by cannabinoid type 1 (CB1) and/or type 2 (CB2) receptor antagonists. Here, using a natural model of central sleep apnea, we examine the effects of dronabinol, alone and in combination with selective antagonists in conscious rats chronically instrumented to stage sleep and measure cessation of breathing.
Adult male Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography on multiple occasions separated by at least 3 days. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections: vehicle; vehicle and CB1 antagonist (AM 251); vehicle and CB2 antagonist (AM 630); vehicle and CB1/CB2 antagonist; dronabinol; dronabinol and CB1 antagonist; dronabinol and CB2 antagonist; and dronabinol and CB1/CB2 antagonist.
Dronabinol decreased the percent time spent in rapid eye movement (REM) sleep. CB receptor antagonists did not reverse this effect. Dronabinol also decreased apneas during sleep, and this apnea suppression was reversed by CB1 or CB1/CB2 receptor antagonism.
Dronabinol's effects on apneas were dependent on CB1 receptor activation, while dronabinol's effects on REM sleep were CB receptor-independent.
阻塞性睡眠呼吸暂停综合征尚无药物治疗方法，但在一项小型试点研究中，屈大麻酚显示出一定前景。在麻醉大鼠中，屈大麻酚通过激活迷走神经传入纤维上的大麻素（CB）受体减轻反射性呼吸暂停；该效应被1型大麻素（CB1）和/或2型大麻素（CB2）受体拮抗剂阻断。在此，我们使用中枢性睡眠呼吸暂停的自然模型，研究屈大麻酚单独使用以及与选择性拮抗剂联合使用对长期植入仪器以分期睡眠和测量呼吸停止的清醒大鼠的影响。
成年雄性Sprague-Dawley大鼠麻醉后，在颅骨双侧植入不锈钢螺钉用于脑电图记录，在颈部肌肉双侧植入线状电极用于肌电图记录。每只动物在至少间隔3天的多个时间点进行多导睡眠图记录。该研究为完全嵌套、重复测量交叉设计，即每只大鼠在以下8次腹腔注射后进行记录：溶剂；溶剂和CB1拮抗剂（AM 251）；溶剂和CB2拮抗剂（AM 630）；溶剂和CB1/CB2拮抗剂；屈大麻酚；屈大麻酚和CB1拮抗剂；屈大麻酚和CB2拮抗剂；屈大麻酚和CB1/CB2拮抗剂。
屈大麻酚减少了快速眼动（REM）睡眠所花费的时间百分比。CB受体拮抗剂并未逆转这种效应。屈大麻酚还减少了睡眠期间的呼吸暂停，并且这种呼吸暂停抑制作用被CB1或CB1/CB2受体拮抗作用所逆转。
屈大麻酚对呼吸暂停的作用依赖于CB1受体激活，而屈大麻酚对REM睡眠的作用与CB受体无关。
