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

Jianjun Xue; Ziqing Xu; Jie Zhang; Huaijing Hou; Long Ge; Kehu Yang

doi:10.1111/jebm.12643

. 2024 Sep 26;17(4):714–728. doi: 10.1111/jebm.12643

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

Jianjun Xue ^1,^2,³, Ziqing Xu ^2,³, Jie Zhang ^2,³, Huaijing Hou ^2,³, Long Ge ¹, Kehu Yang ^1,^4,^5,^6,^✉

PMCID: PMC11684501 PMID: 39325651

Abstract

Objective

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.

Methods

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). I ² value was used to evaluate the heterogeneity. Forest plot was drawn, and p ≤ 0.05 indicates statistically significant difference.

Results

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.

Conclusions

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.

Keywords: cannabinoid type 1 receptor, meta‐analysis, sleep‐wake cycle, systematic review

1. INTRODUCTION

Sleep is a fundamental aspect of health, essential for regulating metabolism, mood, performance, memory consolidation, learning, and appetite. ¹ Chronic sleep deprivation has been associated with various adverse health effects, including diabetes, obesity, hypertension, and cardiovascular diseases. ² Additionally, research has linked chronic sleep deprivation to increased pain sensitivity, resulting in a higher incidence of postoperative pain and an increased risk of chronic pain. ³ , ⁴ Therefore, improving sleep quality is a consistent priority for clinical decision‐makers and healthcare providers. Sleep and wakefulness (W) represent two distinct functional states of the brain. The sleep‐wake cycle is classified into W, nonrapid eye movement (NREM) sleep, also known as slow‐wave sleep, and rapid eye movement (REM) sleep, also known as paradoxical sleep. The regulation and maintenance of these states are influenced by circadian rhythm and external environmental changes. ⁵

Research on the pharmacological effects of the cannabinoid system on the circadian sleep cycle is currently gaining momentum. ⁶ Cannabinoids encompass natural, endogenous, and synthetic cannabinoids. Their primary mechanism of action involves activating the G‐protein‐coupled receptors cannabinoid type‐1 (CB1R) and cannabinoid type‐2 (CB2R). CB1R is predominantly expressed in the central nervous system, with a wide distribution across the basal ganglia, cerebral cortex, cerebellum, olfactory bulb, and hippocampus. ⁷ Alternatively, CB2R is mainly located in the peripheral immune system, such as the spleen, bones, and skin. ⁸ Multiple studies have demonstrated the significant role CB1R plays in regulating the sleep‐wake cycle. ⁹ , ¹⁰ , ¹¹ For example, Pérez‐Morales et al. ¹¹ showed that injecting an endogenous CB1R agonist, 2‐arachidonoylglycerol (2‐AG), into the lateral hypothalamus of Wistar rats increased the frequency of REM sleep, extended the average duration of NREM sleep, and prolonged total sleep time. The CB1R antagonist AM‐251 reversed these effects when administered alongside 2‐AG. Similarly, Bogáthy et al. found that intraperitoneal injection of AM‐251 in Wistar rats lengthened W but shortened both NREM and REM sleep, without significantly altering sleep latency. ¹⁰ Murillo‐Rodríguez et al. showed that injecting CB1R antagonist SR141716A into sleep‐deprived rats heightened their alertness and reduced sleep recovery following prolonged W. ¹²

Nevertheless, studies on CB1R regulation in rodents have yielded conflicting results. Some experiments suggested a minor effect of CB1R on NREM sleep, while others found no significant impact on sleep duration in rats. ¹³ To address this, this study compiled related research from Chinese and English databases to comprehensively investigate and report the effects of CB1R regulation on the sleep‐wake cycle in rats. This approach aimed to offer novel insights and evidence‐based guidance for the clinical treatment of sleep disorders, as well as the comorbidity of sleep deprivation and pain.

2. METHODS

We registered our study protocol with the International Platform of Registered Systematic Review and Meta‐analysis Protocols (INPLASY) (No. INPLASY202450019). The study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement.

2.1. Inclusion and exclusion criteria

2.1.1. Inclusion criteria

Studies were included if they met the following inclusion criteria: (1) subjects: experimental animals with no restriction on the breed of rats under controlled environments (e.g., light‐dark cycles); (2) intervention: CB1R agonists or antagonists, at any dosage and through any administration route; (3) control group: saline or solvent, with other conditions remaining consistent; (4) outcome indicators: W time, NREM sleep time, REM sleep time, sleep latency, as well as duration and frequency of each sleep stage after drug administration; (5) study design: randomized controlled animal experiments, regardless of whether blinding or allocation concealment was reported.

2.1.2. Exclusion criteria

The studies were excluded if they met one of the following exclusion criteria: (1) non‐Chinese or non‐English literature; (2) studies involving CB1R knockout experiments; (3) studies that involved simultaneous use of CB1R agonists and antagonists in animals; (4) studies utilizing modulators that act indirectly on CB1R; (5) studies with inconsistent outcome measures or incomplete data; (6) purely descriptive studies, personal experiences, conference materials, or similar; (7) if the same study data was published more than once, only the most recent publication was included.

2.2. Literature search

Primary computer‐based searches were conducted in four English databases, namely, Cochrane Library, PubMed, Web of Science, and Embase, alongside four Chinese databases, including the Chinese Biomedicine Literature Database (CBM), China National Knowledge Infrastructure, WanFang Data, and VIP. Additionally, supplementary searches were performed on academic platforms such as Google Scholar, Baidu Scholar, and Muchong.com, along with backward tracking of references from the included studies. The search period spanned from the inception of the databases to November 2023, with the supplementary search extending to January 2024.

Search terms were derived from a review of relevant literature and Cochrane systematic reviews/meta‐analyses. Two researchers conducted systematic searches across various databases, combining subject terms and free‐text keywords. The primary search terms included “cannabinoid 1 receptor agonist,” “cannabinoid agonist,” “cannabinoid receptor 1 antagonist,” “cannabinoid antagonist,” “cannabinoid type 1 receptor,” “CB1 receptor,” “CB1R,” “cannabis,” “tetrahydrocannabinol,” “anandamide,” “WIN 55, 212‐2,” “AM251,” “SR161716A,” “sleep,” “sleep disorder,” “sleep deprivation,” “sleep duration,” “sleep pattern,” “sleep problem,” “sleep interruption,” “REM sleep,” “NREM sleep,” and “wakefulness” (Supplementary Material).

2.3. Literature screening

Search results from all databases were imported into the reference management software (Endnote X9). The “Find Duplicates” function was used to automatically identify and remove duplicates by comparing publication titles, years, and author information. Meanwhile, a manual review was also conducted to remove duplicates further. Subsequently, the titles and abstracts were examined to exclude studies that were irrelevant based on the inclusion and exclusion criteria. A detailed reading of the full text followed to select studies that aligned with the purpose of this study.

2.4. Data extraction

A data extraction form was created based on the study content, including components such as (1) literature information: first author's name, publication year, and publication country; (2) baseline data: animal type, sample size, animal weight, age, gender, light‐dark cycle, and sleep monitoring method; (3) intervention: drug action method, dosage, administration route, and administration period; (4) outcome measures: W time, NREM sleep time and REM sleep time (total time of each phase in a certain period of the sleep wake cycle), sleep latency (the time at which the first NREM or REM fragment appeared after drug administration), frequency and average duration of each sleep stage after drug administration; and (5) information required for assessing potential bias in the studies. Upon incomplete or unclear data, attempts were made to contact the corresponding author via phone or email for additional information.

Both literature screening and data extraction were conducted independently by two trained researchers, with cross‐checking for accuracy. Disagreement was resolved through discussion or, when necessary, by consulting a third party for resolution.

2.5. Risk of bias assessment

The quality of the included studies was evaluated using the SYRCLE's risk of bias tool for animal studies. ¹⁴ This tool was suitable for assessing bias in animal intervention studies. ¹⁵ In this study, the evaluation results were categorized as “low risk,” “uncertain risk,” or “high risk.” Two trained evaluators independently conducted this assessment, cross‐checking for accuracy. In cases of disagreement, a third party was consulted for resolution.

2.6. Statistical analysis

The study employed RevMan 5.3 software from Cochrane to conduct meta‐analyses on the extracted outcome measures. The standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for continuous data to measure effect sizes. Data presented in graphical form were extracted using the Engauge Digitizer software. If studies presented the sleep‐wake cycle in percentages (%), the data was converted to time (minute) using Excel. When the number of rats in the experimental group was not specified, the minimum reported number was used to reduce weighting. All meta‐analysis results were displayed as forest plots. Heterogeneity among studies was assessed (with a significance level of α = 0.1), using the I ² statistic. If p ≤ 0.1 and I ² > 50%, significant heterogeneity was assumed, prompting the use of a random‐effects model. If p > 0.1 and I ² < 50%, indicating small heterogeneity, a fixed‐effects model was instead adopted for meta‐analysis. Stata 12.0 software was used for sensitivity analysis and detecting publication bias (when the number of studies in the literature n > 10). Beggs Test was employed to detect publication bias. The significance level for the meta‐analysis was set to α = 0.05, with p‐values below this threshold indicating statistically significant differences.

3. RESULTS

3.1. Literature screening results

Following the search strategy, a comprehensive search of eight databases identified 3420 relevant articles, with an additional two articles found through supplementary searches on other academic platforms. Ultimately, 16 papers were included in the study. The detailed literature screening process is shown in Figure 1.

3.2. Basic characteristics of the included studies

The study included 16 papers, comprising 15 in English and one in Chinese, with a total of 482 experimental rats. The studies were conducted across five countries, with eight (50%) based in Mexico. Eleven studies utilized Wistar rats, ^{9–12, 16–22} four studies used Sprague Dawley rats, ^23–26 and one study involved Lister‐Hooded rats. ²⁷ The body weight of the rats ranged from 200 to 350 grams, and all were adult males. The experimental settings were controlled. Specifically, all but one study followed a 12 h (h)/12 h light‐dark cycle, ²² while the exception had a 14 h/10 h light‐dark cycle (lights on from 6:00 AM to 8:00 PM). The basic characteristics of these included studies are detailed in Table 1.

TABLE 1.

Basic characteristics of the included studies.

Included study	Country	Animal species (weight, gender)	Assessment method	Drug: mode of action	Administration route	Dosing period	Subgrouping: sample size	Outcome indicator
Herrera‐Solís 2010¹⁶	Mexico	Wistar rats	EEG/EMG	ANA: agonist	Lateral ventricular injection	Single‐dose continuous administration: Once per day for 15 consecutive days	Single administration: vehicle, ANA (1 µg), ANA (2 µg), ANA (4 µg) n = 6/group	1, 2, 3, 6
		250–280; all M		OLE: agonist			Single administration: vehicle, AM‐251 (3.2 µg), AM‐251 (6.4 µg), AM‐251 (12.8 µg) n = 6/group
				AM‐251: antagonist			Continuous administration: vehicle, ANA (2 µg), OLE (25 µg)
							n = 6/group
Bogáthy 2019a 17	Hungary	Wistar rats	EEG/EMG	AM‐251: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 6	3
		300–330; all M					AM‐251 (5 mg/kg) n = 6
							AM‐251 (10 mg/kg) n = 6
Bogáthy 2019b 10	Hungary	Wistar rats	EEG/EMG	AM‐251: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 6	3
		300–330; all M					AM‐251 (5 mg/kg) n = 6
							AM‐251 (10 mg/kg) n = 6
Murillo‐Rodríguez 2001¹⁸	Mexico	Wistar rats	EEG/EMG	ANA: agonist	Lateral ventricular injection (i.c.v.)	Single dose	i.c.v.: vehicle n = 10, ANA (1.25 µg) n = 10, SR141716A (3 µg) n = 5	1, 3, 5, 6
Murillo‐Rodríguez 2001¹⁸	Mexico	280–320; all M	EEG/EMG	SR141716: antagonist	Pedunculopontine tegmental nucleus (PPTg)	Single dose	PPTg: vehicle n = 5, ANA (1.25 µg) n = 5, SR141716A (3 µg) n = 5	1, 3, 5, 6
Murillo‐Rodríguez 2016¹²	Mexico	Wistar rats	EEG/EMG	SR141716A: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 10	1, 2, 3
		250–300 g; all M					SR141716A (5 mg/kg) n = 10
							SR141716A (10 mg/kg) n = 10
							SR141716A (20 mg/kg) n = 10
Macías‐Triana 2020¹⁹	Mexico	Wistar rats	EEG/EMG	WIN‐55, 212‐2: agonist	Intraperitoneal injection	Continuous administration: once per day for 14 consecutive days	Vehicle n = 5	1, 2, 3, 4, 5, 6
		250–300 g; all M					WIN55, 212‐2 (0.1 mg/kg) n = 5
							WIN55, 212‐2 (0.3 mg/kg) n = 5
							WIN55, 212‐2 (1 mg/kg) n = 5
Méndez‐Díaz 2013⁹	Mexico	Wistar rats	EEG/EMG	AM‐251: antagonist	Lateral hypothalamic injection	Single dose	Vehicle n = 8	1, 2, 3, 4, 5, 6
		250–350 g; all M		ANA: agonist			ANA (0.5 µg) n = 6
							AM‐251 (0.5 µg) n = 6
Pérez‐Morales 2014²⁰	Mexico	Wistar rats	EEG/EMG	2‐AG: agonist	Lateral hypothalamic injection	Single dose	Vehicle n = 6	1, 2, 3, 4, 5, 6
		250; all M		AM‐251: antagonist			2‐AG (0.01 µg) n = 6
		250; all M		AM‐251: antagonist			AM‐251 (0.01 µg) n = 6
Pérez‐Morales 2013¹¹	Mexico	Wistar rats	EEG/EMG	2‐AG: agonist	Lateral hypothalamic injection	Single dose	Vehicle n = 10	1, 2, 3, 4, 5, 6
		250–300 g; all M		AM‐251: antagonist			2‐AG (0.01 µg) n = 10
							2‐AG (0.1 µg) n = 10
							2‐AG (1 µg) n = 10
							AM‐251 (1.4 µg) n = 10
Pérez‐Morales 2012²¹	Mexico	Wistar rats	EEG/EMG	AM‐251: antagonist	Lateral hypothalamic injection	Single dose	Vehicle n = 10	1, 2, 3, 4, 5, 6
Pérez‐Morales 2012²¹	Mexico	250–300 g; all M	EEG/EMG	AM‐251: antagonist	Lateral hypothalamic injection	Single dose	AM‐251 (1.4 µg) n = 10	1, 2, 3, 4, 5, 6
Puskar 2021²²	United States	Wistar rats	EEG/EMG	WIN‐55, 212‐2: agonist	Medial septum injection	Single dose	Vehicle n = 5	1, 2, 3
		200–250 g; all M		LY 320,135: antagonist			WIN 55, 212‐2 (0.7 µg) n = 6
							LY 320, 135 (0.7 µg) n = 6
Ren 2016²³	China	Sprague Dawley rats	EEG/EMG	(m)VD‐Hpα: agonist	lateral ventricular injection	Single dose	Vehicle n = 8	1, 2, 3, 4, 5, 6
		250–300 g; all M		WIN55, 212‐2: agonist			(m)VD‐Hpα 13.2 nmol n = 7
							(m)VD‐Hpα 20.1 nmol n = 8
							(m)VD‐Hpα 40.2 nmol n = 6
							Vehicle n = 9
							WIN55,212‐2 7.5 nmol n = 7
Calik 2017²⁴	United States	Sprague Dawley rats	EEG/EMG	AM‐251: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 10	1, 2, 3
		∼275 g; all M		Dronabinol: agonist			AM‐251 (5 mg/kg) n = 10
							dronabinol (10 mg/kg) n = 10
Calik 2023²⁵	United States	Sprague Dawley rats	EEG/EMG	AM‐251: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 12	1, 2, 3
		∼275 g; all M		Dronabinol: agonist			AM‐251 (5 mg/kg) n = 12
							dronabinol (10 mg/kg) n = 12
Xie 2023²⁶	China	Sprague Dawley rats	EEG/EMG	(m)VD‐Hpα: agonist	Lateral ventricular injection	Single dose	Vehicle (n = 8–11/group)	1, 2, 3, 4, 5, 6
		250–300 g; all M		WIN55, 212‐2: agonist			(m)VD‐Hpα 6.7 nmol
							(m)VD‐Hpα 13.4 nmol
							(m)VD‐Hpα 20.1 nmol
							WIN55, 212‐2 2.5 nmol
Goonawardena 2011²⁷	United Kingdom	Lister‐Hooded rats	EEG	AM‐251: antagonist	Intraperitoneal injection	Single dose	Vehicle n = 4	1, 2, 3, 4, 5
		250–300 g; all M		WIN‐55, 212‐2: agonist			WIN‐55, 212‐2 (1 mg/kg) n = 4
							AM‐251 (3 mg/kg) n = 4

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Note: (1) W time; (2) NREM sleep time; (3) REM sleep time; (4) sleep latency; (5) average duration of each sleep stage; (6) frequency of each sleep stage.

M: male; EEG: electroencephalogram; EMG: electromyogram; i.c.v.: lateral ventricular injection; PPTg: pedunculopontine tegmental nucleus; ANA: anandamide; OLE: oleamide; Vehicle: solvent group; NA: information not available.

3.3. Quality assessment of the included studies

The included studies utilized varied methodologies, with some lacking specific details, thereby complicating the risk of bias assessment. The included studies either provided insufficient information on the randomization sequence or simply mentioned “randomized,” making it impossible to specify the exact method used. Additionally, it was unclear whether allocation concealment was employed. Regarding blinding, three studies indicated that the researchers were blinded, ^{19, 24, 25} while four studies reported blinding for outcome assessors, ^{19, 24–26} suggesting a low risk of bias. Meanwhile, one study had fewer than five samples per group,²⁷ which was considered high risk for other sources of bias. The risk of bias assessment results for the included studies are displayed in Figure S1.

3.4. Meta‐analysis results

3.4.1. Effect of single CB1R agonist injection on rat sleep‐wake cycle

W time after drug administration

Nine studies investigated the W time during the first 6 h following a CB1R agonist injection, covering 219 rats, with 127 in the experimental group and 92 in the vehicle group. ^{9, 11, 18, 20, 22, 24–27} The heterogeneity test showed p < 0.0001, and I ² = 90%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the W time in the experimental group was reduced during the first 6 h after the CB1R agonist injection, with statistically significant differences (SMD = −2.52, 95% CI (−3.83, −1.22), p = 0.0002) (Figure 2a). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes, as illustrated in Figure S2.

Forest plot for the meta‐analysis comparing W time after the CB1R agonist injection. (a) In the first 6 h; (b) in the first 24 h. W, wakefulness; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Two studies further examined the W time 24 h after the CB1R agonist injection, including 93 rats, with 60 in the experimental group and 33 in the vehicle group.^{23, 26} The heterogeneity test revealed p = 0.14, and I ² = 45%. The fixed‐effects model meta‐analysis indicated that the 24‐h W time after the CB1R agonist injection was shorter in the experimental group than in the vehicle group, with statistically significant differences (SMD = −0.84, 95% CI (−1.31, −0.36), p = 0.0005) (Figure 2b).

NREM sleep time after drug administration

Nine studies investigated the NREM sleep time during the first 6 h following a CB1R agonist injection, encompassing 219 rats, with 127 in the experimental group and 92 in the vehicle group.^{9, 11, 18, 20, 22, 24–27} The heterogeneity test showed p < 0.00001, and I ² = 89%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the NREM sleep time in the experimental group was prolonged during the first 6 h after the CB1R agonist injection, with statistically significant differences (SMD = 1.75, 95% CI (0.54, 2.95), p = 0.005) (Figure 3a). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes (Figure S3).

Forest plot for the meta‐analysis comparing NREM sleep time after the CB1R agonist injection. (a) In the first 6 h; (b) in the first 24 h. NREM, nonrapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Three studies further examined the NREM sleep time 24 h after a CB1R agonist injection, involving 93 rats, with 60 in the experimental group and 33 in the vehicle group.^{9, 23, 26} The heterogeneity test revealed p = 0.14, and I ² = 45%. The fixed‐effects model meta‐analysis indicated no significant difference in the NREM sleep time between the experimental and vehicle groups within 24 h after the CB1R agonist injection (SMD = 0.31, 95% CI (−0.14, 0.76), p = 0.18) (Figure 3b).

REM sleep time after drug administration

Nine studies investigated the REM sleep time during the first 6 h following a CB1R agonist injection, encompassing 219 rats, with 127 in the experimental group and 92 in the vehicle group.^{9, 11, 18, 20, 22, 24–27} The heterogeneity test showed p < 0.00001, and I ² = 92%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the REM sleep time in the experimental group was prolonged during the first 6 h after the CB1R agonist injection, with statistically significant differences (SMD = 1.76, 95% CI (0.26, 3.26), p = 0.02) (Figure 4a). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing unstable outcomes (Figure S4).

Forest plot for the meta‐analysis comparing REM sleep time after the CB1R agonist injection. (a) In the first 6 h; (b) in the first 24 h. REM, rapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Three studies further examined the REM sleep time 24 h after the CB1R agonist injection, involving 107 rats, with 66 in the experimental group and 41 in the vehicle group. ⁹ , ²³ , ²⁶ The heterogeneity test revealed p < 0.00001, and I ² = 93%. The random‐effects model meta‐analysis indicated no significant difference in the NREM sleep time between the experimental and vehicle groups within 24 h after the CB1R agonist injection (SMD = 1.54, 95% CI (−0.68, 3.75), p = 0.17) (Figure 4b).

Sleep latency after drug administration

Five studies examined NREM sleep latency following a CB1R agonist injection, including a total of 153 rats, with 100 in the experimental group and 53 in the vehicle group.^{11, 20, 23, 26, 27} Alternatively, six studies analyzed REM sleep latency after a CB1R agonist injection, involving 179 rats, with 112 in the experimental group and 67 in the vehicle group.^{9, 11, 20, 23, 26, 27} The random‐effects model meta‐analysis indicated that there were no statistically significant differences between the experimental and vehicle groups in either NREM sleep latency (SMD = −1.01, 95% CI (−2.11, 0.10), p = 0.07) or REM sleep latency (SMD = −1.30, 95% CI (−2.74, 0.14), p = 0.08) following the CB1R agonist injection (Figure 5).

Forest plot for the meta‐analysis comparing sleep latency after the CB1R agonist injection. CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Frequency and average duration of REM sleep after drug administration

Six studies compared the REM frequency after a CB1R agonist injection, involving a total of 222 rats, with 139 in the experimental group and 83 in the vehicle group.^{9, 11, 16, 18, 23, 26} The heterogeneity test revealed p < 0.0001, and I ² = 73%. The random‐effects model meta‐analysis suggested that the REM frequency in the experimental group was higher than in the vehicle group, with statistically significant differences (SMD = 1.67, 95% CI (0.98, 2.35), p < 0.00001) (Figure 6).

Forest plot for the meta‐analysis comparing REM frequency after the CB1R agonist injection. REM, rapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Additionally, six studies compared the average REM duration after a CB1R agonist injection, including 170 rats, with 101 in the experimental group and 69 in the vehicle group.^{9, 11, 18, 23, 26, 27} The heterogeneity test revealed p < 0.0001, and I ² = 77%. The random‐effects model meta‐analysis revealed no statistically significant difference in the average REM duration between the experimental group and the vehicle group (SMD = −0.18, 95% CI (−0.93, 0.57), p = 0.64) (Figure 7).

Forest plot for the meta‐analysis comparing average REM duration after the CB1R agonist injection. REM, rapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

3.4.2. Effect of a single CB1R antagonist injection on rat sleep‐wake cycle

W time after drug administration

Ten studies investigated the W time during the first 6 h following a CB1R antagonist injection, covering 178 rats, with 92 in the experimental group and 86 in the vehicle group.^{9, 11, 16, 18, 20–22, 24, 25, 27} The heterogeneity test showed p < 0.00001, and I ² = 87%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the W time in the experimental group was extended during the first 6 h after CB1R antagonist injection, with statistically significant differences (SMD = 1.36, 95% CI (0.29, 2.43), p = 0.01) (Figure 8). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes (Figure S5). In addition, Begg's Test (Z = 1.87, p = 0.062) revealed no significant publication bias (Figure S6).

Forest plot for the meta‐analysis comparing W time in the first 6 h after the CB1R antagonist injection. W, wakefulness; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

NREM sleep time after drug administration

Eleven studies investigated the NREM sleep time during the first 6 h following a CB1R antagonist injection, encompassing 258 rats, with 152 in the experimental group and 106 in the vehicle group. ⁹ , ¹¹ , ¹² , ¹⁶ , ¹⁸ , ²⁰ , ²¹ , ²² , ²⁴ , ²⁵ , ²⁷ The heterogeneity test showed p < 0.00001, and I ² = 90%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the NREM sleep time in the experimental group was shortened during the first 6 h after the CB1R antagonist injection, with statistically significant differences (SMD = −1.73, 95% CI (−2.88, −0.57), p = 0.003) (Figure 9). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes (Figure S7). Begg's Test (Z = −0.98, p = 0.329) revealed no significant publication bias (Figure S8).

Forest plot for the meta‐analysis comparing NREM sleep time in the first 6 h after the CB1R antagonist injection. NREM, nonrapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

REM sleep time after drug administration

Thirteen studies investigated the REM sleep time during the first 6 h following a CB1R antagonist injection, encompassing 274 rats, with 156 in the experimental group and 118 in the vehicle group.^{9–12, 16–18, 20–22, 24, 25, 27} The heterogeneity test showed p < 0.00001, and I ² = 90%. The random‐effects model meta‐analysis showed that compared to the vehicle group, the REM sleep time in the experimental group was reduced during the first 6 h after the CB1R agonist injection, with statistically significant differences (SMD = −2.07, 95% CI (−3.17, −0.96), p = 0.0003) (Figure 10). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes (Figure S9). In addition, Begg's Test (Z = −1.83, p = 0.083) revealed no significant publication bias (Figure S10).

Forest plot for the meta‐analysis comparing REM sleep time in the first 6 h after the CB1R antagonist injection. REM, rapid eye movement; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Frequency and average duration of W after drug administration

Five studies compared the W frequency after a CB1R antagonist injection, involving a total of 105 rats, with 48 in the experimental group and 57 in the vehicle group. ⁹ , ¹¹ , ¹⁸ , ²⁰ , ²¹ The heterogeneity test showed p < 0.00001, and I ² = 90%.The random‐effects model meta‐analysis suggested that after the CB1R antagonist injection, the W frequency in the experimental group was higher than in the vehicle group, with statistically significant differences (SMD = 3.57, 95% CI (1.42, 5.72), p = 0.001) (Figure 11). Sensitivity analysis was conducted by removing one study at a time to assess its impact on the overall effect, revealing stable outcomes (Figure S11).

Forest plot for the meta‐analysis comparing W frequency after CB1R antagonist injection. W, wakefulness; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

Additionally, six studies compared the average W duration after CB1R antagonist injection, including 113 rats, with 52 in the experimental group and 61 in the vehicle group.^{9, 11, 18, 20, 21, 27} The heterogeneity test showed p < 0.00001, and I ² = 89%. The random‐effects model meta‐analysis revealed no statistically significant difference in the average W duration between the experimental group and the vehicle group (SMD = −1.28, 95% CI (−2.85, 0.28), p = 0.11) (Figure 12).

Forest plot for the meta‐analysis comparing average W duration after CB1R antagonist injection. W, wakefulness; CB1R, cannabinoid type‐1 receptor; SD, standardized difference; CI, confidence interval; Std, standardized; IV, inverse variance.

3.4.3. Effect of continuous CB1R agonist injections on sleep‐wake cycle in rats

One study found that when a CB1R agonist was administered to adolescent rats continuously for 14 days, the W time decreased, and the REM time increased in adulthood. ¹⁹

Another study reported that after administering a CB1R agonist to rats for 15 consecutive days, REM time and REM frequency increased following withdrawal. ¹⁶

4. DISCUSSION

Among various mechanisms involved in sleep regulation, the cannabinoid system plays a significant role. ²⁸ In animal studies, exogenous and endogenous cannabinoids generally reduce W and alter NREM and REM sleep times. ²⁹ CB1R, the most abundant Gi/o protein‐coupled receptor in the brain, is involved in retrograde neurotransmission on axons and presynaptic membranes. When activated, CB1R inhibits neurotransmitter release. ³⁰ Some studies have revealed the expression of CB1R in cholinergic neurons, with its activation capable of inducing sleep through ACh activity. ³⁰ , ³¹ Injection of the endogenous CB1R agonist 2‐arachidonoylglycerol (2‐AG) into the lateral hypothalamus of rats has been shown to increase REM sleep time and c‐Fos expression in melanocyte‐concentrating hormone neurons. However, when combined with the CB1R antagonist AM251, this REM sleep increase induced by 2‐AG was blocked. ¹¹ , ²⁰ Due to conflicting findings about the regulation of CB1R in rodent studies, this study employed evidence‐based approaches to provide a comprehensive evaluation of the impact of CB1R on the sleep‐wake cycle in rats. Study developed strict inclusion and exclusion criteria to ensure homogeneity of the studies, reduced confounding bias, and improved comparability and reproducibility between studies. By merging the results of multiple studies, the sample size has been expanded statistically, improving the effectiveness of the test.

The study comprised 16 randomized controlled animal experiments, the experimental groups, which included both CB1R agonists and antagonists, to investigate their effects on the sleep‐wake cycle in rats. The CB1R agonists analyzed in this study included endogenous cannabinoid receptor agonists such as anandamide and 2‐arachidonoylglycerol (2‐AG), synthetic CB1 receptor agonists like WIN‐55, 212‐2, peptide CB1R agonist (m)VD‐hemopressin (α) (VD‐Hpα), and natural cannabinoid cannabicyclol. The results indicated that a single administration of CB1R agonists shortened W time, extended NREM and REM times, increased REM frequency, and promoted sleep. In contrast, CB1R antagonists tended to prolong W time and wake frequency, reduce NREM and REM sleep times, and promote W in the early phase (within the first 6 h). Continuous administration of CB1R agonists to adolescent rats for 14 days resulted in reduced W time and increased REM time after sleep deprivation in adulthood. Similarly, continuous administration of CB1R agonists for 15 days caused increased REM time and REM frequency after withdrawal. These findings reinforce the role of CB1R in the rat sleep‐wake cycle, consistent with the results of a preclinical study conducted by Suraev et al. suggesting potential clinical applications in treating sleep disorders. ⁶

The results of this study found that CB1R agonists and antagonists have vastly different effects on the sleep wake cycle. Excitants promote sleep by activating CB1R, which can reduce the awakening time of animals and make it easier for individuals to enter a sleep state. This may be due to the activation of CB1R by agonists, which affects the neural circuits and neurotransmitter transmission associated with wakefulness. NREM and REM are the two main stages of sleep. CB1R agonists can increase the duration of these two stages, helping to promote deep sleep and dream production. This prolonging effect may help improve sleep quality and promote physical recovery. In addition to prolonging REM time, CB1R agonists can also increase the switching frequency of REM sleep, which may help further consolidate memory and regulate emotions. Antagonists promote wakefulness by blocking the function of CB1R, prolonging wakefulness time and frequency, and shortening NREM and REM sleep time. This may have certain application value for certain scenarios that require staying awake and alert, such as military, medical, etc., but at the same time, attention should be paid to the negative effects it may bring, such as sleep deprivation and fatigue. These findings not only help us to gain a deeper understanding of the regulatory mechanisms of the sleep wake cycle, but also provide important clues and ideas for the development of new therapeutic drugs for sleep disorders.

However, given the differences between rat and human sleep‐wake cycles, these results should be interpreted with caution, with rats primarily sleeping during the day and awake at night. Studies included in this meta‐analysis predominately adopted a 12 h/12 h light‐dark cycle, with heterogeneity mainly stemming from variations in drug administration and sleep recording times. It should also be noted that the outcome indicators in these studies typically focused on a short time frame (less than 24 h), often reporting structural changes in the sleep‐wake cycle within 6 h, while cannabinoid levels can fluctuate throughout the day, potentially leading to varied results depending on when sleep is recorded. ³²

Although this study strictly adhered to the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA statement, ³³ there remain some limitations. First, methodological reporting in the included studies was unclear, making it challenging to assess their quality, resulting in a lower overall evidence quality. Second, the experiments included in the study utilized different drug administration routes, types, and dosages. Because of the limited number of studies, a subgroup analysis of the dose‐response relationship of CB1R modulators was not feasible. Therefore, while the study outlined the role of CB1R in regulating the sleep‐wake cycle, interpretation of the results should be interpreted with caution and in the context of the specific experiment. Third, the included studies used varying reporting formats. For data extraction, this meta‐analysis employed the Engauge Digitizer (http://digitizer.sourceforge.net/usermanual/) to extract information from charts, which could have compromised the accuracy. Lastly, the results were derived from the available RCTs in English and Chinese databases, limited by language and the number of studies. As animal experiments become more rigorous, the conclusion of this study may require reevaluation.

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

ACKNOWLEDGMENTS

This work was supported by the Gansu Province Science and Technology Foundation Project (No. 23JRRA1251).

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

Supporting information

Supporting Information

JEBM-17-714-s001.docx^{(228.5KB, docx)}

Xue J, Xu Z, Zhang J, Hou H, Ge L, Yang K. Systematic review/meta‐analysis on the role of CB1R regulation in sleep‐wake cycle in rats. J Evid Based Med. 2024;17:714–728. 10.1111/jebm.12643

Jianjun Xue and Ziqing Xu contributed equally to this work.

REFERENCES

1. Godos J, Grosso G, Castellano S, Galvano F, Caraci F, Ferri R. Association between diet and sleep quality: a systematic review. Sleep Med Rev. 2021;57:101430. [DOI] [PubMed] [Google Scholar]
2. Institute of Medicine (US) Committee on Sleep Medicine and Research. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Colten HR, Altevogt BM, editors. Washington (DC): National Academies Press (US). 2006. [PubMed]
3. Yang MMH, Hartley RL, Leung AA, et al. Preoperative predictors of poor acute postoperative pain control: a systematic review and meta‐analysis. BMJ Open. 2019;9(4), e025091. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Haack M, Engert LC, Besedovsky L, et al. Alterations of pain pathways by experimental sleep disturbances in humans: central pain‐inhibitory, cyclooxygenase, and endocannabinoid pathways. Sleep. 2023;46(6), zsad061. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Meyer N, Harvey AG, Lockley SW, Dijk DJ. Circadian rhythms and disorders of the timing of sleep. Lancet. 2022;400(10357), 1061–1078. [DOI] [PubMed] [Google Scholar]
6. Suraev AS, Marshall NS, Vandrey R, et al. Cannabinoid therapies in the management of sleep disorders: a systematic review of preclinical and clinical studies. Sleep Med Rev. 2020;53:101339. [DOI] [PubMed] [Google Scholar]
7. Hu SS, Mackie K. Distribution of the endocannabinoid system in the central nervous system. Handb Exp Pharmacol. 2015;231:59–93. [DOI] [PubMed] [Google Scholar]
8. Galiègue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232(1), 54–61. [DOI] [PubMed] [Google Scholar]
9. Méndez‐Díaz M, Caynas‐Rojas S, Arteaga Santacruz V, Ruiz‐Contreras AE, Aguilar‐Roblero R, Prospéro‐García O. Entopeduncular nucleus endocannabinoid system modulates sleep‐waking cycle and mood in rats. Pharmacol Biochem Behav. 2013;107:29–35. [DOI] [PubMed] [Google Scholar]
10. Bogáthy E, Papp N, Vas S, Bagdy G, Tóthfalusi L. AM‐251, a cannabinoid antagonist, modifies the dynamics of sleep‐wake cycles in rats. Front Pharmacol. 2019;10:831. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Pérez‐Morales M, De La Herrán‐Arita AK, Méndez‐Díaz M, Ruiz‐Contreras AE, Drucker‐Colín R, Prospéro‐García O. 2‐AG into the lateral hypothalamus increases REM sleep and cFos expression in melanin concentrating hormone neurons in rats. Pharmacol Biochem Behav. 2013;108:1–7. [DOI] [PubMed] [Google Scholar]
12. Murillo‐Rodríguez E, Machado S, Rocha NB, Budde H, Yuan TF, Arias‐Carrión O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM‐11, in sleep homeostasis. Neuroscience. 2016;339:433–449. [DOI] [PubMed] [Google Scholar]
13. Pava MJ, Makriyannis A, Lovinger DM. Endocannabinoid signaling regulates sleep stability. PLoS One. 2016;11(3), e0152473. [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes‐Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Tao GC, Zhang N, Shang ZZ, et al. Interpretation on examples of SYRCLE' tool for interviewing risk of bias in animal experimentation. Chin J Evid‐Based Cardiovasc Med. 2019;11(03), 292–295. [Google Scholar]
16. Herrera‐Solís A, Vásquez KG, Prospéro‐García O. Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats. Pharmacol Biochem Behav. 2010;95(1), 106–112. [DOI] [PubMed] [Google Scholar]
17. Bogáthy E, Papp N, Tóthfalusi L, Vas S, Bagdy G. Additive effect of 5‐HT2C and CB1 receptor blockade on the regulation of sleep‐wake cycle. BMC Neurosci. 2019;20(1), 14. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Murillo‐Rodríguez E, Cabeza R, Méndez‐Díaz M, Navarro L, Prospéro‐García O. Anandamide‐induced sleep is blocked by SR141716A, a CB1 receptor antagonist and by U73122, a phospholipase C inhibitor. Neuroreport. 2001;12(10), 2131–2136. [DOI] [PubMed] [Google Scholar]
19. Macías‐Triana L, Romero‐Cordero K, Tatum‐Kuri A, et al. Exposure to the cannabinoid agonist WIN 55, 212‐2 in adolescent rats causes sleep alterations that persist until adulthood. Eur J Pharmacol. 2020;874:172911. [DOI] [PubMed] [Google Scholar]
20. Pérez‐Morales M, Fajardo‐Valdez A, Méndez‐Díaz M, Ruiz‐Contreras AE. Prospéro‐García O. 2‐Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation. Neuroreport. 2014;25(18), 1437–1441. [DOI] [PubMed] [Google Scholar]
21. Pérez‐Morales M, Alvarado‐Capuleño I, López‐Colomé AM, Méndez‐Díaz M, Ruiz‐Contreras AE, Prospéro‐García O. Activation of PAR1 in the lateral hypothalamus of rats enhances food intake and REMS through CB1R. Neuroreport. 2012;23(14), 814–818. [DOI] [PubMed] [Google Scholar]
22. Puskar P, Sengupta T, Sharma B, Nath SS, Mallick H, Akhtar N. Changes in sleep‐wake cycle after microinjection of agonist and antagonist of endocannabinoid receptors at the medial septum of rats. Physiol Behav. 2021;237:113448. [DOI] [PubMed] [Google Scholar]
23. Ren WT. Effect of (m)VD‐Hpα, a cannabinod receptor typel agonist,on sleep‐wake states in rats. Lanzhou university. 2016. [Google Scholar]
24. Calik MW, Carley DW. Effects of cannabinoid agonists and antagonists on sleep and breathing in Sprague‐Dawley Rats. Sleep. 2017;40(9), zsx112. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Calik MW, Carley DW. DMSO potentiates the suppressive effect of dronabinol on sleep apnea and REM sleep in rats. J Cannabis Res. 2023;5(1), 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Xie JF, Wang LX, Ren WT, et al. An α‐hemoglobin‐derived peptide (m)VD‐hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor. Front Pharmacol. 2023;14:1213215. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Goonawardena AV, Plano A, Robinson L, Platt B, Hampson RE, Riedel G. A pilot study into the effects of the cb1 cannabinoid receptor agonist WIN55,212‐2 or the antagonist/inverse agonist AM251 on sleep in rats. Sleep Disord. 2011;2011:178469. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Low ZXB, Lee XR, Soga T, Goh BH, Alex D, Kumari Y. Cannabinoids: emerging sleep modulator. Biomed Pharmacother. 2023;165:115102. [DOI] [PubMed] [Google Scholar]
29. Petrunich‐Rutherford ML, Calik MW. Effects of cannabinoid agonists and antagonists on sleep in laboratory animals. Adv Exp Med Biol. 2021;1297:97–109. [DOI] [PubMed] [Google Scholar]
30. Monti JM, Pandi‐Peumal SR, Murillo‐Rodriguez E. Cannabinoids and sleep—molecular, functional and clinical aspects. Springer Nature. 2021:1297. [Google Scholar]
31. Méndez‐Díaz M, Ruiz‐Contreras AE, Cortés‐Morelos J, Prospéro‐García O. Cannabinoids and sleep/wake control. Adv Exp Med Biol. 2021;1297:83–95. [DOI] [PubMed] [Google Scholar]
32. Liedhegner ES, Sasman A, Hillard CJ. Brain region‐specific changes in N‐acylethanolamine contents with time of day. J Neurochem. 2014;128(4), 491–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group . Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Med. 2009;6(7), e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Information

JEBM-17-714-s001.docx^{(228.5KB, docx)}

[jebm12643-bib-0001] 1. Godos J, Grosso G, Castellano S, Galvano F, Caraci F, Ferri R. Association between diet and sleep quality: a systematic review. Sleep Med Rev. 2021;57:101430. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0002] 2. Institute of Medicine (US) Committee on Sleep Medicine and Research. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Colten HR, Altevogt BM, editors. Washington (DC): National Academies Press (US). 2006. [PubMed]

[jebm12643-bib-0003] 3. Yang MMH, Hartley RL, Leung AA, et al. Preoperative predictors of poor acute postoperative pain control: a systematic review and meta‐analysis. BMJ Open. 2019;9(4), e025091. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0004] 4. Haack M, Engert LC, Besedovsky L, et al. Alterations of pain pathways by experimental sleep disturbances in humans: central pain‐inhibitory, cyclooxygenase, and endocannabinoid pathways. Sleep. 2023;46(6), zsad061. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0005] 5. Meyer N, Harvey AG, Lockley SW, Dijk DJ. Circadian rhythms and disorders of the timing of sleep. Lancet. 2022;400(10357), 1061–1078. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0006] 6. Suraev AS, Marshall NS, Vandrey R, et al. Cannabinoid therapies in the management of sleep disorders: a systematic review of preclinical and clinical studies. Sleep Med Rev. 2020;53:101339. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0007] 7. Hu SS, Mackie K. Distribution of the endocannabinoid system in the central nervous system. Handb Exp Pharmacol. 2015;231:59–93. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0008] 8. Galiègue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232(1), 54–61. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0009] 9. Méndez‐Díaz M, Caynas‐Rojas S, Arteaga Santacruz V, Ruiz‐Contreras AE, Aguilar‐Roblero R, Prospéro‐García O. Entopeduncular nucleus endocannabinoid system modulates sleep‐waking cycle and mood in rats. Pharmacol Biochem Behav. 2013;107:29–35. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0010] 10. Bogáthy E, Papp N, Vas S, Bagdy G, Tóthfalusi L. AM‐251, a cannabinoid antagonist, modifies the dynamics of sleep‐wake cycles in rats. Front Pharmacol. 2019;10:831. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0011] 11. Pérez‐Morales M, De La Herrán‐Arita AK, Méndez‐Díaz M, Ruiz‐Contreras AE, Drucker‐Colín R, Prospéro‐García O. 2‐AG into the lateral hypothalamus increases REM sleep and cFos expression in melanin concentrating hormone neurons in rats. Pharmacol Biochem Behav. 2013;108:1–7. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0012] 12. Murillo‐Rodríguez E, Machado S, Rocha NB, Budde H, Yuan TF, Arias‐Carrión O. Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM‐11, in sleep homeostasis. Neuroscience. 2016;339:433–449. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0013] 13. Pava MJ, Makriyannis A, Lovinger DM. Endocannabinoid signaling regulates sleep stability. PLoS One. 2016;11(3), e0152473. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0014] 14. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes‐Hoitinga M, Langendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0015] 15. Tao GC, Zhang N, Shang ZZ, et al. Interpretation on examples of SYRCLE' tool for interviewing risk of bias in animal experimentation. Chin J Evid‐Based Cardiovasc Med. 2019;11(03), 292–295. [Google Scholar]

[jebm12643-bib-0016] 16. Herrera‐Solís A, Vásquez KG, Prospéro‐García O. Acute and subchronic administration of anandamide or oleamide increases REM sleep in rats. Pharmacol Biochem Behav. 2010;95(1), 106–112. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0017] 17. Bogáthy E, Papp N, Tóthfalusi L, Vas S, Bagdy G. Additive effect of 5‐HT2C and CB1 receptor blockade on the regulation of sleep‐wake cycle. BMC Neurosci. 2019;20(1), 14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0018] 18. Murillo‐Rodríguez E, Cabeza R, Méndez‐Díaz M, Navarro L, Prospéro‐García O. Anandamide‐induced sleep is blocked by SR141716A, a CB1 receptor antagonist and by U73122, a phospholipase C inhibitor. Neuroreport. 2001;12(10), 2131–2136. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0019] 19. Macías‐Triana L, Romero‐Cordero K, Tatum‐Kuri A, et al. Exposure to the cannabinoid agonist WIN 55, 212‐2 in adolescent rats causes sleep alterations that persist until adulthood. Eur J Pharmacol. 2020;874:172911. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0020] 20. Pérez‐Morales M, Fajardo‐Valdez A, Méndez‐Díaz M, Ruiz‐Contreras AE. Prospéro‐García O. 2‐Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation. Neuroreport. 2014;25(18), 1437–1441. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0021] 21. Pérez‐Morales M, Alvarado‐Capuleño I, López‐Colomé AM, Méndez‐Díaz M, Ruiz‐Contreras AE, Prospéro‐García O. Activation of PAR1 in the lateral hypothalamus of rats enhances food intake and REMS through CB1R. Neuroreport. 2012;23(14), 814–818. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0022] 22. Puskar P, Sengupta T, Sharma B, Nath SS, Mallick H, Akhtar N. Changes in sleep‐wake cycle after microinjection of agonist and antagonist of endocannabinoid receptors at the medial septum of rats. Physiol Behav. 2021;237:113448. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0023] 23. Ren WT. Effect of (m)VD‐Hpα, a cannabinod receptor typel agonist,on sleep‐wake states in rats. Lanzhou university. 2016. [Google Scholar]

[jebm12643-bib-0024] 24. Calik MW, Carley DW. Effects of cannabinoid agonists and antagonists on sleep and breathing in Sprague‐Dawley Rats. Sleep. 2017;40(9), zsx112. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0025] 25. Calik MW, Carley DW. DMSO potentiates the suppressive effect of dronabinol on sleep apnea and REM sleep in rats. J Cannabis Res. 2023;5(1), 30. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0026] 26. Xie JF, Wang LX, Ren WT, et al. An α‐hemoglobin‐derived peptide (m)VD‐hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor. Front Pharmacol. 2023;14:1213215. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0027] 27. Goonawardena AV, Plano A, Robinson L, Platt B, Hampson RE, Riedel G. A pilot study into the effects of the cb1 cannabinoid receptor agonist WIN55,212‐2 or the antagonist/inverse agonist AM251 on sleep in rats. Sleep Disord. 2011;2011:178469. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0028] 28. Low ZXB, Lee XR, Soga T, Goh BH, Alex D, Kumari Y. Cannabinoids: emerging sleep modulator. Biomed Pharmacother. 2023;165:115102. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0029] 29. Petrunich‐Rutherford ML, Calik MW. Effects of cannabinoid agonists and antagonists on sleep in laboratory animals. Adv Exp Med Biol. 2021;1297:97–109. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0030] 30. Monti JM, Pandi‐Peumal SR, Murillo‐Rodriguez E. Cannabinoids and sleep—molecular, functional and clinical aspects. Springer Nature. 2021:1297. [Google Scholar]

[jebm12643-bib-0031] 31. Méndez‐Díaz M, Ruiz‐Contreras AE, Cortés‐Morelos J, Prospéro‐García O. Cannabinoids and sleep/wake control. Adv Exp Med Biol. 2021;1297:83–95. [DOI] [PubMed] [Google Scholar]

[jebm12643-bib-0032] 32. Liedhegner ES, Sasman A, Hillard CJ. Brain region‐specific changes in N‐acylethanolamine contents with time of day. J Neurochem. 2014;128(4), 491–506. [DOI] [PMC free article] [PubMed] [Google Scholar]

[jebm12643-bib-0033] 33. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group . Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Med. 2009;6(7), e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

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

Jianjun Xue

Ziqing Xu

Jie Zhang

Huaijing Hou

Long Ge

Kehu Yang

Abstract

Objective

Methods

Results

Conclusions

1. INTRODUCTION

2. METHODS

2.1. Inclusion and exclusion criteria

2.1.1. Inclusion criteria

2.1.2. Exclusion criteria

2.2. Literature search

2.3. Literature screening

2.4. Data extraction

2.5. Risk of bias assessment

2.6. Statistical analysis

3. RESULTS

3.1. Literature screening results

FIGURE 1.

3.2. Basic characteristics of the included studies

TABLE 1.

3.3. Quality assessment of the included studies

3.4. Meta‐analysis results

3.4.1. Effect of single CB1R agonist injection on rat sleep‐wake cycle

W time after drug administration

FIGURE 2.

NREM sleep time after drug administration

FIGURE 3.

REM sleep time after drug administration

FIGURE 4.

Sleep latency after drug administration

FIGURE 5.

Frequency and average duration of REM sleep after drug administration

FIGURE 6.

FIGURE 7.

3.4.2. Effect of a single CB1R antagonist injection on rat sleep‐wake cycle

W time after drug administration

FIGURE 8.

NREM sleep time after drug administration

FIGURE 9.

REM sleep time after drug administration

FIGURE 10.

Frequency and average duration of W after drug administration

FIGURE 11.

FIGURE 12.

3.4.3. Effect of continuous CB1R agonist injections on sleep‐wake cycle in rats

4. DISCUSSION

ACKNOWLEDGMENTS

CONFLICT OF INTEREST STATEMENT

Supporting information

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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