Systematic review/meta-analysis on the role of CB1R regulation in sleep-wake cycle in rats

A systematic review/meta-analysis was conducted to investigate the effect of cannabinoid type-1 receptor (CB1R) regulation on the sleep-wake cycle of rats and to provide new ideas and evidence-based basis for clinical research on the treatment of sleep disorders.

We searched Cochrane Library, PubMed, Web of Science, Embase, Chinese Biomedicine Literature Database (CBM), China National Knowledge Infrastructure, WanFang, and VIP databases for relevant papers, about the effects of CB1R agonists/antagonists on sleep-wake cycle in rats, from inception to November 2023. Two reviewers performed study screening, data extraction, and risk of bias assessment using the SYRCLE's risk of bias tool. Meta-analysis was performed using RevMan 5.3 software. Heterogeneity test was performed on the included studies (Test standard α = 0.1). I² value was used to evaluate the heterogeneity. Forest plot was drawn, and p ≤ 0.05 indicates statistically significant difference.

A total of 16 trials involving 484 experimental rats were included. The methodological quality evaluation results showed that the overall quality of the included studies was low. The results of the meta-analysis showed that single administration of CB1R agonists could shorten the wakefulness (W) time in the first 6 h (h) (standardized mean difference (SMD) = -2.52, 95% confidence interval (CI) (-3.83, -1.22), p = 0.0002) and 24 h (SMD = -0.84, 95% CI (-1.31, -0.36), p = 0.0005) after administration, prolong nonrapid eye movement sleep (NREM) time (SMD = 1.75, 95% CI (0.54, 2.95), p = 0.005) and rapid eye movement sleep (REM) time (SMD = 1.76, 95% CI (0.26, 3.26), p = 0.02), and increase REM frequency after administration (SMD = 1.67, 95% CI (0.98, 2.35), p < 0.00001), these results were all statistically different. There were no significant differences in sleep latency and average duration of REM. Single administration of CB1R antagonists prolonged the first 6 h W time after administration (SMD = 1.36, 95%CI (0.29, 2.43), p = 0.01), shortened the first 6 h NREM time (SMD = -1.73, 95% CI (-2.88, -0.57), p = 0.003) and REM time (SMD = -2.07, 95% CI (-3.17, -0.96), p = 0.0003) after administration, and increased the frequency of W after administration (SMD = 3.57, 95% CI (1.42, 5.72), p = 0.001). There was no statistical difference in the average duration of W. REM time and REM frequency increased after continuous CB1R agonist withdrawal.

According to the existing evidence, CB1R played a pivotal role in regulating the sleep-wake cycle in rats. CB1R agonists tended to reduce W time, increase NREM and REM sleep times, boost REM frequency, and promote sleep. Conversely, CB1R antagonists could increase the duration and frequency of W, shorten NREM and REM sleep times, and promote W.