ArticleLiterature Review

The Emerging Role of the Endocannabinoid System in the Sleep-Wake Cycle Modulation

Authors:
  • Universidad Anáhuac Mayab. Mérida, Yucatán. México
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Abstract

The endocannabinoid system comprises amides, esters and ethers of long chain polyunsaturated fatty acids. Narachidonoylethanolamide (anandamide; ANA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids (endocannabinoids) ligands for the cannabinoid family of G-protein-coupled receptors named CB1 and CB2. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and behave as retrograde signaling messengers, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters systems. The two principal enzymes that are responsible for the metabolism of ANA and 2-AG are fatty acid amide hydrolase and monoacylglycerol lipase, respectively. Pharmacological experiments have shown that the administration of endocannabinoids induce cannabimimetic effects, including sleep promotion. This review will focus on some of the current evidence of the pharmacological potential of the endocannabinoid system on sleep modulation.

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... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). ...
... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). ...
... The endogenous cannabinoid (endocannabinoid) system regulates numerous circadian processes including food intake, peripheral metabolism, and body temperature via the suprachiasmatic nucleus (Vaughn et al. 2010;Ho et al. 2008;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011) and is involved in the sleep/wake cycle, (Kesner and Lovinger 2020;Murillo-Rodriguez et al. 2011). The endocannabinoid system consists of lipid mediators that act upon specific receptors, including the nervous system (Kesner and Lovinger 2020;Prospero-Garcia et al. 2016;Murillo-Rodriguez et al. 2011). It can also influence temperature regulation, fat storage, mood and behaviour regulation, sensory perception, motor activity, nervous system modulation, and endocrine and gastrointestinal (GI) function (Vaughn et al., 2010) -all previously shown to have an effect on sleep (Vaughn et al., 2010). ...
Article
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Background Sleep is essential for wellbeing, yet sleep disturbance is a common problem linked to a wide range of health conditions. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide proposed to promote better sleep via potential interaction with the endocannabinoid system. Methods This double-blind, randomised study on 103 adults compared the efficacy and tolerability of 8 weeks of daily supplemented PEA formulation (350 mg Levagen + ®) to a placebo. Sleep quality and quantity were measured using wrist actigraphy, a sleep diary and questionnaires. Results At week 8, PEA supplementation reduced sleep onset latency, time to feel completely awake and improved cognition on waking. After 8 weeks, both groups improved their sleep quality and quantity scores similarly. There was no difference between groups at baseline or week 8 for sleep quantity or quality as measured from actigraphy or sleep diaries. Conclusion These findings support PEA as a potential sleeping aid capable of reducing sleep onset time and improving cognition on waking. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12618001339246. Registered 9th August 2018.
... Given its ubiquitous expression in multiple brain areas, CB1 receptors modulate a variety of functions including learning and memory, mood, stress, anxiety, locomotion, social behaviors, arousal state, food intake, pain and sensory perception (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Marsicano and Lafenêtre, 2009;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). In contrast, CB2 receptors are primarily found in the immune system at the periphery (Munro et al., 1993). ...
... neuropeptides, nitric oxide and endocannabinoids) in this brain region remains poorly investigated. One of the most important neuromodulatory systems in the brain is the ECS (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). However, the only few studies investigating the contribution of CB1 receptors in the PC were performed in the posterior part (pPC) and the available evidence does not allow determining the exact impact of the ECS in anterior par of PC (aPC) circuits and in related olfactory-guided behaviors (Ghosh et al., 2018;Zenko et al., 2011). ...
... In neurons, activation of pre-synaptic CB1 receptors results in the decrease of neurotransmitter release, inducing several forms of ECS-dependent synaptic plasticity (Araque et al. 2017;Busquets-Garcia, Bains, and Marsicano 2018;Castillo et al. 2012;Kano et al. 2009;Zou and Kumar 2018). Moreover, given the wide expression of CB1 receptors in multiple brain areas, the ECS modulates a large variety of cognitive processes, including learning and memory, anxiety, locomotion, food intake, sensory perception and many others (Chaouloff et al., 2011;Corcoran et al., 2015;Lutz et al., 2015;Morena and Campolongo, 2014;Murillo-Rodriguez et al., 2011;Soria-Gómez et al., 2014a;Wei et al., 2017). ...
Thesis
Impliquée dans de nombreuses fonctions comportementales, l'olfaction joue un rôle majeur quant à l'orientation de nos actions. Les odeurs communiquent avec le système nerveux central par l'intermédiaire de récepteurs situés dans l'épithélium olfactif du nez qui génèrent des signaux neuronaux, transmis et traités dans de nombreuses régions du cerveau. En particulier, le cortex piriforme antérieur (CPa) est une région olfactive importante impliquée dans la perception et l'intégration des odeurs. Étant donné le rôle du principal récepteur aux cannabinoïdes de type 1 (CB1) dans les fonctions sensorielles et les processus de mémoire, nous avons émis l'hypothèse que ces récepteurs pourraient moduler le traitement des odeurs dans le CPa. Pour ce faire, en combinant des approches anatomiques, électrophysiologiques et pharmacologiques, nous avons d'abord caractérisé la répartition des récepteurs CB1 et évalué leur capacité à réguler les circuits du CPa. Nous avons observé que ces récepteurs sont principalement exprimés dans les interneurones GABAergiques et que leur activation régule la transmission et la plasticité inhibitrice. Puis, nous avons cherché à déterminer le rôle et l'impact des récepteurs CB1 dans le traitement des odeurs dans le CPa. Grâce à une technique d'imagerie calcique in vivo, nous avons montré que l'altération de la signalisation des récepteurs CB1 affecte l'activité des neurones du CPa en réponse aux odeurs. En agissant très semblablement sur les circuits inhibiteurs locaux, nous avons mis en évidence que le fonctionnement physiologique des récepteurs CB1 dans le CPa est nécessaire pour le rappel d’une information olfactive apprise dans un contexte appétitif mais pas aversif. De façon générale, ces travaux permettent de mieux comprendre comment les récepteurs CB1 modulent les processus olfactifs dans le CPa.
... Process S can be viewed as representative of sleep promotion, which increases during wakefulness and declines during sleep, whereas Process C can be viewed as representative of the regulation of wake-promoting biological rhythms (Borbely, 1982;Joiner, 2018). Process S and Process C continuously interact, with many neurotransmitters, including endocannabinoids (ECBs), playing a role in both sleep regulation processes (Murillo-Rodríguez et al., 2011). These neurotransmitters also play a regulatory role in other aspects of human health. ...
... The ECB system has become an emerging target of interest due to its purported role in both sleep regulation and cognition. The ECB system modulates sleep by inducing the release of wake-promoting neurotransmitters (Murillo-Rodríguez et al., 2011). ECBs (i.e., anandamide (AEA) and oleamide (OLA)) are expressed in a diurnal manner, including in brain regions which regulate cognition (Murillo-Rodriguez et al., 2006). ...
Article
Objectives: Both sleep and cognition are partially modulated by the endocannabinoid (ECB) system. Cannabis has been reported to have effects on sleep and cognition. This review aims to summarize the recent literature on the ECB system, the role of cannabis and the ECB system on sleep regulation and cognition. Further, this review will identify existing gaps in knowledge and suggest potential targets for future research. Methods: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reports were identified by searching PubMed/MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO for articles published through September 2021 for studies with data available on aspects of cognition, cannabis, or the ECB system, and sleep or circadian rhythms (CRs). Results: We identified 6 human and 6 animal studies to be eligible for inclusion in this review. Several human studies found that cannabis use is not associated with changes in sleep quality or cognitive function. However, individual cannabinoids appeared to have independent effects on cognition and sleep; THC alone decreased cognitive performance and increased daytime sleepiness, whereas CBD alone had no effect on sleep or cognition. Animal studies demonstrated that manipulation of the ECB system altered activity and cognitive function, some of which appeared to be dependent on the light/dark cycle. Conclusion: The sleep-wake cycle and CRs are both likely modulated by the ECB system, potentially resulting in effects on cognition, however this area is critically understudied.
... For instance, the eCB system is thought to play an active role in regulatory processes, such as pain perception, memory, and sleep modulation [25,26]. Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. ...
... Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. Despite the perceived benefits of cannabinoids, there remains a lack of placebo-controlled trials that have examined the effects of the drug using validated sleep measures or objective sleep outcomes [11][12][13]. ...
Preprint
BACKGROUND Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. OBJECTIVE We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. METHODS Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. RESULTS Overall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P <.001) and predominant sativa strains (estimated mean difference 0.74, SE 0.16; 95% CI 0.43-1.06; adjusted P <.001). Indica hybrid strains also presented a greater reduction in insomnia symptomology than CBD strains (mean difference 0.52, SE 0.12; 95% CI 0.29-0.74; adjusted P <.001) and predominant sativa strains (mean difference 0.67, SE 0.16; 95% CI 0.34-1.00; adjusted P =.002). CONCLUSIONS Medicinal cannabis users perceive a significant improvement in insomnia with cannabinoid use, and this study suggests a possible advantage with the use of predominant indica strains compared with predominant sativa strains and exclusively CBD in this population. This study emphasizes the need for randomized placebo-controlled trials assessing the efficacy and safety profile of cannabinoids for the treatment of insomnia.
... For instance, the eCB system is thought to play an active role in regulatory processes, such as pain perception, memory, and sleep modulation [25,26]. Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. ...
... Although the neurobiological basis of cannabis for sleep is still being understood, overlaps between the neuronal circuitry of sleep and wake states and the eCB system suggest that cannabinoids can contribute to sleep-related mechanisms and physiology [27][28][29]. Therefore, the eCB system has become a growing target in sleep research [25][26][27][28][29][30]. Despite the perceived benefits of cannabinoids, there remains a lack of placebo-controlled trials that have examined the effects of the drug using validated sleep measures or objective sleep outcomes [11][12][13]. ...
Article
Full-text available
Background Insomnia is a prevalent condition that presents itself at both the symptom and diagnostic levels. Although insomnia is one of the main reasons individuals seek medicinal cannabis, little is known about the profile of cannabinoid use or the perceived benefit of the use of cannabinoids in daily life. Objective We conducted a retrospective study of medicinal cannabis users to investigate the use profile and perceived efficacy of cannabinoids for the management of insomnia. Methods Data were collected using the Strainprint app, which allows medicinal cannabis users to log conditions and symptoms, track cannabis use, and monitor symptom severity pre- and postcannabis use. Our analyses examined 991 medicinal cannabis users with insomnia across 24,189 tracked cannabis use sessions. Sessions were analyzed, and both descriptive statistics and linear mixed-effects modeling were completed to examine use patterns and perceived efficacy. ResultsOverall, cannabinoids were perceived to be efficacious across all genders and ages, and no significant differences were found among product forms, ingestion methods, or gender groups. Although all strain categories were perceived as efficacious, predominant indica strains were found to reduce insomnia symptomology more than cannabidiol (CBD) strains (estimated mean difference 0.59, SE 0.11; 95% CI 0.36-0.81; adjusted P
... Moreover, the blockade of the CB 1 cannabinoid receptor by pharmacological means facilitates alertness. Lastly, current evidence suggests the link between the endocannabinoid system and sleep disturbances, including narcolepsy [12][13][14][15][49][50][51][52][53][54][55][56]. ...
... The endocannabinoid system is integrated by the CB 1 /CB 2 cannabinoid receptors, the endogenous ligands AEA and 2-AG, and their respective metabolizing and synthetizing enzymes, as well as membrane transporter [1,2]. This neurobiological system has been described in multiple human biological samples, including the brain [1,2,[6][7][8][9][10][11], suggesting its role on the regulation of a broad neurobiological processes such as the sleep-wake cycle [12][13][14][15][49][50][51][52][53][54][55][56][57][58], which is also driven by a variety of neuroanatomical brain areas, neurochemicals, and circadian and homeostatic factors [16][17][18][19][20][21][22][23][24][25][26]. On the other hand, the sleep disorders are the pathological feature of sleep patterns described by the International Classification of Sleep Disorders [27], including insomnia and sleep-related breathing disorders, such as OSA. ...
Article
Full-text available
The endocannabinoid system is a neurobiological signaling network that is present in the human biological systems, including the brain. This neurobiological system comprises cannabinoid receptors, endogenous ligands, as well as enzymatic synthesis, degradation and transport of endocannabinoids and has been suggested as a modulator of multiple physiological processes, including the sleep–wake cycle. On the other hand, the COVID-19 pandemic, originated by the novel coronavirus SARS-CoV-2, has caused global catastrophes in economic, social, and health spheres. COVID-19 is a multi-organ disease with a broad spectrum of health complications, such as respiratory infections leading to respiratory-related symptoms and disorders. The development, approval, and application of vaccines against SARS-CoV-2 is ongoing; however, there are increasing reports of prolonged effects after COVID-19 infection, including respiratory and neurological sequelae. Here, I provide a comprehensive review of the current literature on the endocannabinoid system and their role in sleep modulation. Whilst I discuss relevant considerations for the high risk for developing sleep disorders related to respiratory failures, such as obstructive sleep apnea (OSA) in recovered COVID-19-infected subjects. Finally, I propose a framework that integrates the analysis of the components of the endocannabinoid system as prognostic biomarkers of the likely OSA after COVID-19 infection.
... That is, if phenotypes are genetically correlated, the relationship between those phenotypes can be partially explained by a common genetic liability (pleiotropy and shared genetics), implying that the genetic influences on one phenotype also have an influence on another phenotype. There is increasing evidence of a genetic relationship between cannabis use and sleep deficits, which may be biologically centered on the endocannabinoid system's involvement in the circadian sleep-wake cycle [47][48][49]. Additionally, disruption of circadian genes might disturb the reward processing system, which can influence substance use [50,51]. ...
... One possible explanation for this genetic relationship could be that disturbances of circadian rhythm genes might interrupt the reward processing system, which could influence substance use [50,51]. Another supported explanation could be that the endocannabinoid system is involved in the circadian sleep-wake cycle, such that endocannabinoids influence sleep behaviors and their levels can vary with the time of day and other circadian-related factors [47][48][49]116]. Along these lines, several of the genes and genetic pathways found to be significant in sleep-related variable GWAS [57,[59][60][61][62] have been associated with cannabis use and cannabinoid activity [63-66, 68, 69, 117-120]. ...
Article
Study objectives: Estimate the genetic relationship of cannabis use with sleep deficits and eveningness chronotype. Methods: We used linkage disequilibrium score regression (LDSC) to analyze genetic correlations between sleep deficits and cannabis use behaviors. Secondly, we generated sleep deficit polygenic risk scores (PRS) and estimated their ability to predict cannabis use behaviors using linear and logistic regression. Summary statistics came from existing genome wide association studies (GWAS) of European ancestry that were focused on sleep duration, insomnia, chronotype, lifetime cannabis use, and cannabis use disorder (CUD). A target sample for PRS prediction consisted of high-risk participants and participants from twin/family community-based studies (European ancestry; n = 760, male = 64%; mean age = 26.78 years). Target data consisted of self-reported sleep (sleep duration, feeling tired, and taking naps) and cannabis use behaviors (lifetime ever use, number of lifetime uses, past 180-day use, age of first use, and lifetime CUD symptoms). Results: Significant genetic correlation between lifetime cannabis use and eveningness chronotype (rG = 0.24, p < 0.001), as well as between CUD and both short sleep duration (<7 h) (rG = 0.23, p = 0.017) and insomnia (rG = 0.20, p = 0.020). Insomnia PRS predicted earlier age of first cannabis use (OR = 0.92, p = 0.036) and increased lifetime CUD symptom count (OR = 1.09, p = 0.012). Conclusion: Cannabis use is genetically associated with both sleep deficits and an eveningness chronotype, suggesting that there are genes that predispose individuals to both cannabis use and sleep deficits.
... Recent evidence suggests that genetics may play a role in the etiology of the relationship between early cannabis use and adult sleep problems [18], and that there could be a common genetic liability for cannabis use and sleep problems that explain their relationship. Several lines of evidence are consistent with this common genetic model: the presence of genes believed to be involved with circadian rhythm/sleep in genomewide associations studies of lifetime cannabis use [39][40][41], clock gene genetic variants that are associated with cannabis addiction [42], and the possible role of the endocannabinoid system in the circadian rhythm/sleep-wake cycle [43][44][45][46]. Further research is needed on the possible shared genetics between cannabis use and clinical sleep outcomes such as insomnia. ...
... A recent study using similar twin models found that shared genetics may play a role in the etiology of the relationship between early cannabis use and adult sleep duration [18], and there are various additional lines of evidence consistent with this common genetic liability theory. Endocannabinoids may play a large part in this relationship, as the endocannabinoid system may be involved in the circadian sleep-wake cycle [43][44][45][46]. Endocannabinoids influence sleep, and their levels vary with time of day [45]. ...
Article
Full-text available
Study Objectives Estimate the genetic and environmental influences on the relationship between onset of regular cannabis use and young adult insomnia. Methods In a population-based twin cohort of 1882 twins (56% female, mean age = 22.99, SD = 2.97) we explored the genetic/environmental etiology of the relationship between onset of regular cannabis use and insomnia-related outcomes via multivariate twin models. Results Controlling for sex, current depression symptoms, and prior diagnosis of an anxiety or depression disorder, adult twins who reported early onset for regular cannabis use (age 17 or younger) were more likely to have insomnia (β = 0.07, p = 0.024) and insomnia with short sleep on weekdays (β = 0.08, p = 0.003) as young adults. We found significant genetic contributions for the onset of regular cannabis use (a2 = 76%, p < 0.001), insomnia (a2 = 44%, p < 0.001), and insomnia with short sleep on weekdays (a2 = 37%, p < 0.001). We found significant genetic correlations between onset of regular use and both insomnia (rA = 0.20, p = 0.047) and insomnia with short sleep on weekdays (rA = 0.25, p = 0.008) but no significant environmental associations between these traits. Conclusions We found common genetic liabilities for early onset of regular cannabis use and insomnia, implying pleiotropic influences of genes on both traits.
... In addition, it was found that CBD enhanced the extracellular levels of dopamine collected from nucleus accumbens, whereas an increase in c-Fos expression was detected in waking-related brain areas, such as hypothalamus and dorsal raphe nucleus (Murillo-Rodríguez et al. 2006a, b). Similar findings were observed when CBD was injected into the lateral hypothalamus of rats during the lights-on period (Murillo-Rodríguez et al. 2008, 2011a. Recently, Hsiao et al. (2012) reported that CBD blocked anxiety-induced REMS suppression. ...
... The sleep-wake cycle is controlled by multiple neurochemical substrates, including exogenous and endogenous cannabinoids (Buonamici et al. 1982;Carlini and Cunha 1981;Feinberg et al. 1975Feinberg et al. , 1976Freemon 1972;Monti 1977;Murillo-Rodríguez et al. 2006a, b, 2008, 2011aNicholson et al. 2004;Pivik et al. 1972). In this chapter, we revised that phytocannabinoids modulate the sleep-wake cycle. ...
Chapter
Marijuana is a colloquial name given to Cannabis sativa, which has been used for diverse purposes, including as a therapeutical element for multiple health issues. The neurobiological effects of C. sativa involve a complex biological machinery including receptors, named CB1 and CB2 cannabinoid receptors. These receptors recognize endogenous cannabinoid-like compounds, such as anandamide and 2-arachinonolglycerol which seems to display sleep-inducing properties. Along decades, the study of the putative role of exogenous and endogenous cannabinoids in sleep modulation has brought critical data. Since endocannabinoids have been described in sleep-related brain areas, intriguing issues regarding whether hypothalamic substrates, such as MHC, may be interacting with the endocannabinoids have been raised.
... Sleep is a complex behavior regulated by homeostatic and circadian factors that involve diverse brain circuits, endogenous molecules, and multiple neurotransmitter systems [42,43] as well as the endocannabinoid system, which includes endogenous ligands, receptors, enzymes and transporters [1,2,8,20]. Current evidence suggests that the endocannabinoid system modulates the sleep-wake cycle [25,36,38,[44][45][46][47][48]. While evidence regarding the role on sleep modulation of the endocannabinoid system elements, such as ANA [38,45,46], CB 1 cannabinoid receptor [46], or FAAH [40,48] have been suggested, further studies were needed to describe the effects of AMT inhibition on the sleep-wake cycle. ...
... Current evidence suggests that the endocannabinoid system modulates the sleep-wake cycle [25,36,38,[44][45][46][47][48]. While evidence regarding the role on sleep modulation of the endocannabinoid system elements, such as ANA [38,45,46], CB 1 cannabinoid receptor [46], or FAAH [40,48] have been suggested, further studies were needed to describe the effects of AMT inhibition on the sleep-wake cycle. Although a previous pharmacological report has shown that the AMT inhibitor VDM-11 promotes sleep and increases c-Fos expression in sleep-related brain areas such as the PVA [25], the pharmacological action of OMDM-2 on sleep remained unknown. ...
Article
The family of the endocannabinoid system comprises endogenous lipids (such as anandamide, [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and the putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-​(4-​hydroxy-​2-​methylphenyl)-​5Z,​8Z,​11Z,​14Z-​eicosatetraenamide (VDM-11; 10, 20 or 30μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation.
... Furthermore, our study confirmed the significant role of the ECS in sleep regulation. Consistent with previous research [46], we found reduced levels of AEA and 1-AG in insomnia mice. This reduction in AEA and 1-AG is largely due to the antagonistic relationship between the ECS and the HPA axis. ...
Article
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Baihe Dihuang Tang (BDT), is a traditional Chinese medicinal formulation historically utilized to manage various health conditions, including insomnia. This therapeutic use of BDT for treating insomnia is rooted in its potential to regulate the gut microbiota, neuroendocrine, and serotonin systems, which may collectively contribute to its effectiveness. This study aims to explore the anti‐insomnia effects of BDT, and focus on its underlying mechanisms, emphasizing the potential interplay with gut microbiota, neuroendocrine, and serotonin pathways. An insomnia mouse model was induced using p‐chlorophenylalanine (PCPA). Subjects received varying doses of BDT or a saline solution as a control. Behavioral assessment was conducted via the open field test and elevated plus maze test. Hypothalamic monoamine neurotransmitter levels were quantified using ELISA kits. Neurosteroid levels in brain and serum samples were determined through high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS). Gut microbiota composition was evaluated using 16S rRNA amplicon sequencing. PCPA‐induced insomnia led to significant alterations in neurosteroids, monoamine neurotransmitters, and gut microbiota composition. BDT treatment markedly improved behavioral parameters in insomniac mice, evidenced by enhanced motility and reduced sleep latency compared to controls. BDT administration restored neurosteroid and monoamine neurotransmitter dose‐dependently, suggesting potential for neuroendocrine system homeostasis restoration. BDT‐treated mice exhibited significant gut microbiota composition changes, including reduced Acidobacteria, increased Fusobacteria and Firmicutes at the phylum level, and decreased Alistipes at the genus level, compared to the insomnia model group. BDT effectively rectifies gut dysbiosis and mitigates neuroendocrine and serotonin system dysfunctions induced by insomnia, emerging as a promising therapeutic candidate for insomnia management.
... Similarly, research on PEA has highlighted its capacity to enhance wakefulness upon administration into the lateral hypothalamus or the dorsal raphe nucleus of rats, as reported by Murillo-Rodriguez et al. (2011) [49]. This enhancement came at the expense of both NREM and REM sleep stages, further underscoring the arousing effects of PEA within the central nervous system. ...
Article
Full-text available
The endogenous cannabinoid system (ECS) plays a critical role in the regulation of various physiological functions, including sleep, mood, and neuroinflammation. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinomimimetics, and some N-acylethanolamides, particularly palmitoyethanolamide, have emerged as potential therapeutic agents for the management of sleep disorders. THC, the psychoactive component of cannabis, may initially promote sleep, but, in the long term, alters sleep architecture, while CBD shows promise in improving sleep quality without psychoactive effects. Clinical studies suggest that CBD modulates endocannabinoid signaling through several receptor sites, offering a multifaceted approach to sleep regulation. Similarly, palmitoylethanolamide (PEA), in addition to interacting with the endocannabinoid system, acts as an agonist on peroxisome proliferator-activated receptors (PPARs). The favorable safety profile of CBD and PEA and the potential for long-term use make them an attractive alternative to conventional pharmacotherapy. The integration of the latter two compounds into comprehensive treatment strategies, together with cognitive–behavioral therapy for insomnia (CBT-I), represents a holistic approach to address the multifactorial nature of sleep disorders. Further research is needed to establish the optimal dosage, safety, and efficacy in different patient populations, but the therapeutic potential of CBD and PEA offers hope for improved sleep quality and general well-being.
... G-protein coupled receptor found on cells in the central and peripheral nervous system -involved in processes of mood, appetite, learning, memory and pain. Research to date has demonstrated that the ECS is involved in homeostasis and regulation via neuromodulatory activity, physiological processes such as digestion [42], immune function [43], nociception [44], appetite regulation [45], cardiovascular and respiratory function [46] and sleep wake cycles [47]. ...
Preprint
Full-text available
There is a growing interest in the endocannabinoid system and the gut microbiota. Both areas have been suggested to play a role in endometriosis, however this is yet to be studied comprehensively. The purpose of this narrative review is to identify the gaps in endometriosis research in the context of these two areas. It underscores the limited knowledge regarding the involvement of the endocannabinoid system and gut microbiota in endometriosis. Further research in these areas is essential to unlock the therapeutic potential of cannabis and enhance the understanding of endometriosis pathogenesis.
... Research to date has demonstrated that the ECS is involved in homeostasis and regulation via neuromodulatory activity, physiological processes such as digestion [42], immune function [43], nociception [44], appetite regulation [45], cardiovascular and respiratory function [46] and sleep wake cycles [47]. ...
Preprint
Full-text available
There is a growing interest in the endocannabinoid system and the gut microbiota. Both areas have been suggested to play a role in endometriosis, however this is yet to be studied comprehensively. The purpose of this narrative review is to identify the gaps in endometriosis research in the context of these two areas. It underscores the limited knowledge regarding the involvement of the endocannabinoid system and gut microbiota in endometriosis. Further research in these areas is essential to unlock the therapeutic potential of cannabis and enhance the understanding of endometriosis pathogenesis.
... The eCB system is involved in many physiological functions, such as learning, memory, plasticity, inflammation, and appetite (Gambi et al. 2005, Basavarajappa et al. 2009). Further, endogenous cannabinoids affect the body's circadian rhythm, i.e. the sleep-wake cycle (Murillo-Rodriguez et al. 2012). Preclinical studies showed that the eCB system is involved in sleep regulation and circadian rhythms through CB1 receptors in the suprachiasmatic nucleus in the brain (Acuna Goycolea 2021). ...
Article
Among individuals with alcohol use disorder (AUD), it is estimated that the majority suffer from persistent sleep disturbances for which few candidate medications are available. Our aim wass to critically review the potential for cannabidiol (CBD) as a treatment for AUD-induced sleep disturbance. As context, notable side effects and abuse liability for existing medications for AUD-induced sleep disturbance reduce their clinical utility. CBD modulation of the endocannabinoid system and favorable safety profile have generated substantial interest in its potential therapeutic use for various medical conditions. A number of preclinical and clinical studies suggest promise for CBD in restoring the normal sleep-wake cycle and in enhancing sleep quality in patients diagnosed with AUD. Based on its pharmacology and the existing literature, albeit primarily preclinical and indirect, CBD is a credible candidate to address alcohol-induced sleep disturbance. Well-designed RCTs will be necessary to test its potential in managing this challenging feature of AUD.
... Sleep is an important aspect of adolescent development, playing a crucial role in physiology, cognition, and mental health. 148,149 The endocannabinoid system is thought to be involved in the modulation of circadian rhythm and the sleep/wake cycle, 150,151 particularly through the influence of cannabinoids on CB1 receptors. 152,153 Heavy cannabis activity is linked to desensitization, and decreased CB1 efficacy 154,155 and blocking of the CB1 receptors have been found to facilitate waking in rodent models specifically. ...
Article
The current review highlights the available research related to cannabis and indicators of physical health in a variety of domains. Various studies have found associations between cannabis use with pulmonary, cardiovascular, gastrointestinal, and endocrine function as well as body mass index and sleep. At this time, more research is needed to understand the influence of cannabis use on physical health, particularly among adolescent samples.
... Participant sleep-wake regimens were not accounted for and may have had impact as circadian rhythms of endogenous cannabinoid signaling are associated with sleep-wake rhythms. [44][45][46] Similarly, there was a wide variation in participants' cannabis use history of 1-25 years, and may have influenced pharmacokinetic parameters. 22,27,29 This study evaluated a single dose; therefore, considerations for other dosing may be beneficial. ...
Article
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Background An oral route of administration for tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ⁹-THC, 11-OH-THC, and 11-nor-9-carboxy-Δ⁹-THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. Materials and Methods Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design. To evaluate the pharmacokinetics of Δ⁹-THC, CBD, 11-OH-THC, and THC-COOH, blood was collected at pre-dose (t=0) and 10, 20, 30, and 45, min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h post-dose after a single dose of Solutech (10.0 mg Δ⁹-THC, 9.76 mg CBD) or MCT (10.0 mg Δ⁹-THC, 9.92 mg CBD). Heart rate and blood pressure were measured at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Relationships between cannabis use history, body mass index, sex, and pharmacokinetic parameters were investigated. Safety was assessed before and at 48 h post-acute dose. Results Acute consumption of Solutech provided a significantly greater maximum concentration (Cmax), larger elimination and absorption rate constants, faster time to Cmax and lag time, and half-life for all analytes compared to MCT-oil (p<0.001). In addition, cannabis use history had a significant influence on the pharmacokinetic parameters of CBD, Δ⁹-THC, 11-OH-THC, and THC-COOH. On average, participants with later age of first use had higher Δ⁹-THC, CBD, and THC-COOH Cmax and later time-to-Cmax and half-life for Δ⁹-THC, CBD, THC-COOH, and 11-OH-THC than those with earlier age of first use (p≤0.032). Those with more years of recreational cannabis use had higher area under the curve for Δ⁹-THC and CBD, Cmax for CBD, and longer 11-OH-THC half-life than those with less (p≤0.048). Conclusion This study demonstrated that consumption of Solutech enhanced most pharmacokinetics parameters measured compared to MCT-oil. Participant's cannabis use history, including their age of first use and number of years using cannabis significantly impacted pharmacokinetic parameters investigated. Acute consumption of both products was found to be safe and well tolerated. The results suggest that Solutech may optimize bioavailability from cannabis formulations.
... However, we have reviewed the current understanding of the endogenous compounds that participate in the modulation of the sleep-wake cycle. For example, alertness has been linked to the action of noradrenaline, serotonin, dopamine, ACh, histamine, and glutamate [107][108][109][110][111][112], whereas SWS seems to be the result of the activity of GABA, adenosinergic, prostaglandinergic neurons and REMS sleep is generated and maintained by the interaction of multiple neurotransmitter systems such as ACh and lipids including the endocannabinoid anandamide [113][114][115][116][117][118][119][120][121]. The variety of molecules related to the modula- Fig. (4). ...
Article
The sleep-wake cycle is the result of the activity of a multiple neurobiological network interaction. Dreaming feature is one interesting sleep phenomena that represents sensorial components, mostly visual perceptions, accompanied with intense emotions. Further complexity has been added to the topic of the neurobiological mechanism of dreams generation by the current data that suggests the influence of drugs on dream generation. Here, we discuss the review on some of the neurobiological mechanism of the regulation of dream activity, with special emphasis on the effects of stimulants on dreaming.
... Both fatty acids play a role in serotonin regulation (39), and the serotonergic system has been shown to play a critical role in sleep initiation and sleep maintenance (40). While AA has also been hypothesized to be involved in sleep-wake modulation (41,42), our findings do not suggest a prominent role of AA (or LA) in sleep duration or difficulty falling sleeping. ...
Article
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Background: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. Objectives: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. Methods: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. Results: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. Conclusions: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.
... Recently, the field of the endocannabinoids has grown in popularity since the discovery of endogenous cannabinoid receptors in the brain (Matsuda et al., 1990) and their most relevant endocannabinoids ligands. Multiple studies have reported its role on a variety of brain structures and cognitive functions like memory, appetite, metabolism, immune system, mood and sleep (Murillo-Rodriguez et al., 2011;Tanasescu and Constantinescu, 2010;Zanettini et al., 2011). ...
Article
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Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.
... Nonetheless, some animal studies have pointed to a possible beneficial role of AA on sleep (38). The association also has biological plausibility, because AA is a precursor of anandamide, a cannabinoid that is involved in the initiation of sleep (39). ...
Article
Background: Delayed sleep timing and short sleep duration represent a significant public health burden in adolescents. Whether intake of nutrients affects the pineal gland, where sleep/wake cycles are regulated, remains unclear. Objectives: In a cross-sectional analysis, we investigated whether plasma concentrations of DHA and arachidonic acid (AA), long-chain fatty acids that can be obtained through diet, were related to sleep timing and duration in adolescents. Methods: The study population included 405 Mexico City adolescents (mean age ± SD = 14.2 ± 2.1 y; 48% males) who took part in a 2015-2016 follow-up visit as a part of an ongoing cohort study. Fatty acid concentrations were measured in plasma using GLC, as a percentage of total fatty acids. Sleep midpoint and duration were assessed with 7-d wrist actigraphy. We categorized DHA and AA plasma concentrations into quartiles (Q1-Q4; Q4 = highest fatty acids). We conducted cross-sectional linear regression analysis with sleep characteristics as separate outcomes and quartiles of DHA and AA as exposures, adjusting for sex, age, and BMI z-scores. Results: Mean ± SD plasma DHA (as percentage of total fatty acids) was 1.2 ± 0.4%, whereas mean ± SD plasma AA was 6.2 ± 1.5%. In adjusted analysis, higher plasma DHA was linearly associated with longer sleep duration on the weekends; to illustrate, those in Q4 compared with Q1 had 32 min longer duration (95% CI: 7, 57; P trend = 0.005). Higher DHA was also associated with earlier sleep timing during weekdays and weekends, although in a nonlinear fashion. The largest difference was a 0.75-h (45-min) later sleep midpoint in Q2 compared with Q4 (95% CI: 0.36, 1.14). Conclusions: Plasma DHA was associated with earlier sleep timing and longer weekend sleep duration in Mexican adolescents. Whether DHA supplementation improves sleep in adolescent populations deserves consideration in randomized trials.
... In addition, the endocannabinoid system is integrated by several molecular elements, including the enzymes that synthesize/degrade anandamide (fatty acid hydrolase [FAAH]) or 2-AG (monoacylglycerol lipase [MAGL]), the anandamide membrane transporter (AMT) and the receptor channel TRPV1 (Transient Receptor Potential Vanilloid 1; [78][79][80][81][82]). Along the decades, preclinical studies have shown that the endocannabinoid system exerts critical neurobiological functions, some of them, with clinical relevance, including the control of the sleep-wake cycle [80,[83][84][85][86][87][88][89][90][91][92][93]]. ...
Article
Full-text available
Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.
... For example, microinjections of CBD into a lateral ventricle (icv) or lateral hypothalamus produced significant increases in the extracellular DA in the NAc. 87,88 However, intra-NAc microinjection of CBD produced an inhibitory effect on VTA DA neuronal activity by itself 89 and attenuated amphetamine-induced locomotor sensitization and VTA DA neuronal sensitization. 89,90 Although the authors proposed that 5-HT 1A mechanisms may underlie intra-NAc CBD-induced reduction in NAc DA, 90,91 there is no direct evidence to support it. ...
Article
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A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity. Cannabidiol is a recently U.S. FDA approved medication for the treatment of epilepsy. In this study, we found that it is also effective in controlling food‐taking behavior in rats and mice largely by activation of cannabinoid CB2 receptor.
... Intracerebroventricular administration of the eCB anandamide (ANA) during the lights-on period caused diminution in wakefulness, while increased non-REMS and REMS in rats. This effect was more evident when ANA was injected directly into the PPT nucleus, and SR141716a prevented this effect [37,38]. Experimental evidence indicates that the activation of the CB 1 receptors promotes the release of acetylcholine (ACh) in cortical and hippocampal areas [39]. ...
Article
Full-text available
Background Previous data show that serotonin 2C (5-HT2C) and cannabinoid 1 (CB1) receptors have a role in the modulation of sleep–wake cycle. Namely, antagonists on these receptors promoted wakefulness and inhibited rapid eye movement sleep (REMS) in rodents. The interaction of these receptors are also present in other physiological functions, such as the regulation of appetite. Blockade of 5-HT2C receptors modulat the effect of CB1 receptor antagonist, presumably in consecutive or interdependent steps. Here we investigate, whether previous blockade of 5-HT2C receptors can affect CB1 receptor functions in the sleep–wake regulation. Results Wistar rats were equipped with electroencephalography (EEG) and electromyography (EMG) electrodes. Following the recovery and habituation after surgery, animals were injected intraperitoneally (ip.) with SB-242084, a 5-HT2C receptor antagonist (1.0 mg/kg) at light onset (beginning of passive phase) followed by an injection with AM-251, a CB1 receptor antagonist (5.0 or 10.0 mg/kg, ip.) 10 min later. EEG, EMG and motor activity were analyzed for the subsequent 2 h. Both SB-242084 and AM-251 increased the time spent in active wakefulness, while decreased the time spent in non-REMS and REMS stages in the first 2 h of passive phase. In combination, the effect of the agents were additive, furthermore, statistical analysis did not show any interaction between the effects of these drugs in the modulation of vigilance stages. Conclusions Our results suggest that 5-HT2C receptor blockade followed by blockade of CB1 receptors evoked additive effect on the regulation of sleep–wake pattern.
... Anandamide may act as a neurotransmitter promoting sleep by enhancing the levels of the sleep-inducing molecule adenosine. 56,57 Furthermore, CB2 receptor agonists may protect against cerebral ischemia and reperfusion injury by decreasing the inflammatory and immune response and promoting a vasodilatation effect. 58 Anandamide levels have been analyzed in plasma from groundhogs using LC−MS analysis, but no differences were seen between summer active and torpid animals. ...
Article
Syrian hamster undergoes a reversible hyperphosphorylation of protein tau during hibernation, providing a unique natural model that may unveil the physiological mechanisms behind this critical process involved in the development of Alzheimer’s disease and other tauopathies. The hibernation cycle of these animals fluctuates between two stages: 34 days of torpor bouts interspersed with periods of euthermia called arousals that last several hours. In this study, we investigated for the first time the metabolic changes in brain tissue during hibernation. A total of 337 metabolites showed statistically significant differences during hibernation. Based on these metabolites, several pathways were found to be significantly regulated and, therefore, play a key role in the regulation of hibernation processes. The increase in the levels of ceramides containing more than 20 C atoms was found in torpor animals, reflecting a higher activity of CerS2 during hibernation, linked to neurofibrillary tangle generation and structural changes in the Golgi apparatus. Our results open up the debate about the possible significance of some metabolites during hibernation, which may possibly be related to tau phosphorylation and dephosphorylation events. In general, this study may provide insights into novel neuroprotective agents since the alterations described throughout the hibernation process are reversible.
... More recent studies have demonstrated that n-3 LC-PUFA derivatives of endocannabinoids also exist [63][64][65]. Endocannabinoid action via cannabinoid 1 and 2 receptors impacts a wide range of biological functions including energy balance and metabolism, mood, memory, sleep, reproduction, thermoregulation and immune function [63][64][65][66][67][68][69][70][71][72][73][74][75]. Endocannabinoids can also be metabolized by cyclooxygenases, lipoygenases, and p450 epoxygenases to form other biologically-active complex lipids [65,76,77]. ...
Article
Full-text available
Background: Dietary essential omega-6 (n-6) and omega-3 (n-3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and elongase enzymes encoded by FADS and ELOVL genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These n-6 and n-3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes. Methods: This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene-diet interactions that may lead to excess levels of n-6 LC-PUFAs and deficiencies of n-3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize n-3 LC-PUFA supplementation for individuals and populations. Conclusions: The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized n-3 LC-PUFA supplementation regimens to prevent and manage human disease.
... Con-sciousness has been studied in neuroscience from different experimental perspectives, including electrophysiological correlates and neuroanatomical attempts [76][77][78][79]. Based on the given theoretical definition of consciousness, it can be inferred that current experimental data have demonstrated that the manipulation of the endocannabinoid system modulates consciousness by regulating alertness, fear, anxiety, pain perception, learning and memory, and sleep [80][81][82][83][84][85][86]. However, confirmatory experiments are needed to describe whether the FAAH, MAGL or AMT play relevant roles in the level of consciousness. ...
Article
Background & objective: Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Conclusion: Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.
... Moreover, OEA infusion into the lateral hypothalamus reduced c-Fos expression in the cells of this area , although, the kind of neurotransmitter these cells synthesize and release was not determined. Regarding PEA, it also increases wakefulness when administered into the lateral hypothalamus, and into the dorsal raphe nucleus of rats, at the expense of NREM and REM sleep (Murillo-Rodriguez et al., 2011). In animal models, eCBs, such as AEA and 2-AG, reduce wakefulness while increasing sleep Murillo-Rodrıíguez et al., 1998;Pérez-Morales et al., 2013). ...
... However, cannabis and two of its major components, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are associated with disrupted sleep using objective measures (3). THC exerts its effects on the brain and body by binding to CB1 and CB2 receptors in the endocannabinoid system, which modulates the sleep-wake cycle (4). CB1 receptor antagonists increase wakefulness and reduce rapid eye movement (REM) time in animal studies (5)(6)(7)(8). ...
Article
Background: Cannabis has been shown to affect sleep in humans. Findings from animal studies indicate that higher endocannabinoid levels promote sleep, suggesting that chronic use of cannabis, which downregulates endocannabinoid activity, may disrupt sleep. Objectives: This study sought to determine if past-year cannabis use and genes that regulate endocannabinoid signaling, FAAH rs324420 and CNR1 rs2180619, predicted sleep quality. As depression has been previously associated with both cannabis and sleep, the secondary aim was to determine if depressive symptoms moderated or mediated these relationships. Methods: Data were collected from 41 emerging adult (ages 18-25) cannabis users. Exclusion criteria included Axis I disorders (besides SUD) and medical and neurologic disorders. Relationships were tested using multiple regressions, controlling for demographic variables, past-year substance use, and length of cannabis abstinence. Results: Greater past-year cannabis use and FAAH C/C genotype were associated with poorer sleep quality. CNR1 genotype did not significantly predict sleep quality. Depressive symptoms moderated the relationship between cannabis use and sleep at a nonsignificant trend level, such that participants with the higher cannabis use and depressive symptoms reported the more impaired sleep. Depressive symptoms mediated the relationship between FAAH genotype and sleep quality. Conclusions: This study demonstrates a dose-dependent relationship between chronic cannabis use and reported sleep quality, independent of abstinence length. Furthermore, it provides novel evidence that depressive symptoms mediate the relationship between FAAH genotype and sleep quality in humans. These findings suggest potential targets to impact sleep disruptions in cannabis users.
... Alguns desses traços, sobretudo déficits em interação social e na extinção de memórias aversivas, aparecem em camundongos knockout para o gene que codifica o receptor de canabinoide do tipo 1 (CB1) e em ratos nascidos de mães tratadas com valproato durante a gravidez -que são modelos animais para o estudo de autismo correlatos aos casos humanos de autismo decorrentes de mulheres tratadas com valproato durante a gravidez (Chakrabarti et al., 2006;Dubreucq et al., 2011;Haller et al., 2004;Markram et al., 2007;Markram et al., 2008;Marsicano et al., 2002). Estas informações são consistentes com um grande número de evidências correlacionando o receptor CB1 com comportamento emocional e social tanto em roedores trole da plasticidade neuronal, na interação social, da cognição, na percepção de dor e outras informações sensoriais, no controle da ansiedade, e na suscetibilidade a convulsões que são fatores caracteristicamente comprometidos em pacientes portadores da Síndrome do X frágil (Ashton e Moore, 2011;Busquets-Garcia et al., 2013;Crowe et al., 2014;Giuffrida e Piomelli, 2000;Hill e Gorzalka, 2009;Kerr et al., 2013;Lightbody e Reiss, 2009;Marco e Laviola, 2011;Marco e Viveros, 2009;Marsicano e Lafenetre, 2009;Morena e Campolongo, 2014;Murillo-Rodriguez et al., 2011;Parolaro et al., 2010;Penagarikano et al., 2007;Pfeiffer e Huber, 2009;Puente et al., 2011;Ridaura-Ruiz et al., 2009;Tsiouris e Brown, 2004). ...
... Alguns desses traços, sobretudo déficits em interação social e na extinção de memórias aversivas, aparecem em camundongos knockout para o gene que codifica o receptor de canabinoide do tipo 1 (CB1) e em ratos nascidos de mães tratadas com valproato durante a gravidez -que são modelos animais para o estudo de autismo correlatos aos casos humanos de autismo decorrentes de mulheres tratadas com valproato durante a gravidez (Chakrabarti et al., 2006;Dubreucq et al., 2011;Haller et al., 2004;Markram et al., 2007;Markram et al., 2008;Marsicano et al., 2002). Estas informações são consistentes com um grande número de evidências correlacionando o receptor CB1 com comportamento emocional e social tanto em roedores trole da plasticidade neuronal, na interação social, da cognição, na percepção de dor e outras informações sensoriais, no controle da ansiedade, e na suscetibilidade a convulsões que são fatores caracteristicamente comprometidos em pacientes portadores da Síndrome do X frágil (Ashton e Moore, 2011;Busquets-Garcia et al., 2013;Crowe et al., 2014;Giuffrida e Piomelli, 2000;Hill e Gorzalka, 2009;Kerr et al., 2013;Lightbody e Reiss, 2009;Marco e Laviola, 2011;Marco e Viveros, 2009;Marsicano e Lafenetre, 2009;Morena e Campolongo, 2014;Murillo-Rodriguez et al., 2011;Parolaro et al., 2010;Penagarikano et al., 2007;Pfeiffer e Huber, 2009;Puente et al., 2011;Ridaura-Ruiz et al., 2009;Tsiouris e Brown, 2004). ...
... Based on findings that CB1Rs can control release of ACh (Gifford & Ashby, 1996;Gessa et al., 1997;Acquas et al., 2000Acquas et al., , 2001Kathmann et al., 2001), a role for eCBs in generation of state has been previously proposed (Murillo-Rodriguez et al., 1998;Murillo-Rodriguez, 2008). While evidence of inhibition of ACh release has been presented, rises noted in the hippocampus and cortical regions via a CB1R-mediated mechanism (Acquas et al., 2000(Acquas et al., , 2001 have led to the suggestion that CB1R-mediated actions in the pons, stimulated by endogenous production of eCBs, could lead to activation of cholinergic LDT neurons, leading to brainstem rises in ACh and thereby, via activation of the caudal reticular formation, participate in generation of the sleep states (Murillo-Rodriguez et al., 2011). The presynaptically invoked CB1R-mediated decrease in inhibition seen in the present study could play a role in CB1Rmediated increases in release of ACh, along with glutamate, when LDT activity is high via a feed-forward mechanism. ...
Article
Marijuana, which acts within the endocannabinoid (eCB) system as an agonist of the cannabinoid type 1 receptor (CB1R), exhibits addictive properties and has powerful actions on the state of arousal of an organism. The laterodorsal tegmental nucleus (LDT), as a component of the reticular activating system, is involved in cortical activation and is important in the development of drug addiction-associated behaviours. Therefore, eCBs might exert behavioural effects by actions on the LDT; however, it is unknown whether eCBs have actions on neurons in this nucleus. Accordingly, whole-cell voltage- and current-clamp recordings were conducted from mouse brain slices, and responses of LDT neurons to the CB1R agonist WIN-2 were monitored. Our results showed that WIN-2 decreased the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs). Ongoing activity of endogenous eCBs was confirmed as AM251, a potent CB1R antagonist, elicited sIPSCs. WIN-2 reduced the firing frequency of LDT neurons. In addition, our RT-PCR studies confirmed the presence of CB1R transcript in the LDT. Taken together, we conclude that CB1Rs are functionally active in the LDT, and their activation changes the firing frequency and synaptic activity of neurons in this nucleus. Therefore, endogenous eCB transmission could play a role in processes involving the LDT, such as cortical activation and motivated behaviours and, further, behavioural actions of marijuana are probably mediated, in part, via cellular actions within the LDT induced by this addictive and behavioural state-altering drug.
... A megnövekedett CB1 receptor aktiváció csökkenti a stressz válasz mértékét, amely kannabinoid agonisták adagolásával és a lebontó enzim, a zsírsavamid hidroláz (FAAH) gátlásával is elérhető (Patel et al., 2004). A kannabinoid agonisták továbbá, a CB1 recptorok közvetítésével, alvást indukáló hatással rendelkeznek (Murillo-Rodriguez et al., 2011). Az anandamid intracerebroventriculáris adagolása patkányokban alvást indukáló hatással rendelkezett, így csökkentette az ébrenlét és növelte mind a NREM, mind a REMs mennyiségét (Murillo-Rodriguez et al., 1998). ...
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The recreational drug ecstasy is widely used among dance clubbers for its acute euphoric and entactogenic effects. Ecstasy exerts its acute effects by increasing the extracellular concentration of monoamines in the brain by reversing the functions of reuptake mechanisms. These elevations in extracellular monoamine concentrations result in wake promoting effects, body hyperthermia and reductions in local cerebral blood flow. However, on the long-run, ecstasy reduces serotonin concentration and density of serotonergic markers in several brain areas. Functional deficits, like sleep disturbances, anxiogenic- and aggressive behavioral responses and mood disorders also may occur. However, one of the most prominent adverse effects is related to the cognitive functions. Following ecstasy use attenuated retro- and prospective memory and defective higher order cognitive functions can be observed, especially in heavy users. Several studies indicated the involvement of the endocannabinoid system, the sleep regulating centers and the hypothalamic-pituitary-adrenal axis based on or parallel to serotonergic damage in these processes. Recent evidence, however, also showed that changes in one of the latter systems can influence the functions of each other. In this review we summarize the related literature, and propose a complex mechanism for the long-lasting cognitive deficits following heavy ecstasy use.
... On the other hand, a novel potential method in the treatment for compulsive eating disorders may be taken into consideration. Some noteworthy findings suggest that CB 1 activation could also induce sleep promotion (Santucci et al., 1996;Murillo-Rodriguez et al., 2011). It may suggest the existence of an alternative mode of the DORAs' hypnotic action in the brain. ...
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Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.
... Along these lines, the EC system has been implicated in mediating some of the effects of the general anesthetic propofol (Patel et al., 2003), but there are currently no data available as to the effects of urethane on the EC system, making data from the in vivo studies difficult to interpret in light of conflicting results. Additionally, a nascent but growing body of evidence has linked the EC system to the regulation of the sleep/wake cycle (for review see Murillo- Rodriguez et al., 2011). As a consequence, future studies should be sensitive to the possible interactions between the EC system and the state of the organism under study. ...
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Endometriosis, a chronic condition affecting around 10–14% of women, is challenging to manage, due to its complex pathogenesis and limited treatment options. Research has suggested a potential role of the gut microbiota and the endocannabinoid system in the development and progression of endometriosis. This narrative review aims to explore the role of, and any potential interactions between, the endocannabinoid system (ECS) and the gut microbiota in endometriosis. This review found that both the ECS and microbiota influence endometriosis, with the former regulating inflammation and pain perception and the latter influencing immune responses and hormonal balance. There is evidence that a dysregulation of the endocannabinoid system and the gut microbiota influence endometriosis symptoms and progression via changes in CB1 receptor expression and increased circulating levels of endocannabinoids. Microbial imbalances in the gut, such as increases in Prevotella, have been directly correlated to increased bloating, a common endometriosis symptom, while increases in E. coli have supported the bacterial contamination hypothesis as a potential pathway for endometriosis pathogenesis. These microbial imbalances have been correlated with increases in inflammatory markers such as TNF-α and IL-6, both often raised in those with endometriosis. Protective effects of the ECS on the gut were observed by increases in endocannabinoids, including 2-AG, resulting in decreased inflammation and improved gut permeability. Given these findings, both the ECS and the gut microbiota may be targets for therapeutic interventions for endometriosis; however, clinical studies are required to determine effectiveness.
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Introduction: There is widespread literature on the interaction between cannabis use and sleep, yet the mechanisms that underlie this relationship are not well understood. Several factors lead to inconsistencies in this relationship suggesting a nuanced interaction between cannabis and sleep. An important question that remains to be addressed is the temporal relationship between disrupted sleep and cannabis use. This literature review summarizes the existing literature on the association between disrupted sleep and cannabis toward the goal of addressing the question of the chronology of these reported effects. Materials and Methods: We conducted a review of the literature using PubMed to summarize current knowledge on the association between cannabis use and sleep in humans. Results: We identified 31 studies on the association of cannabis use and sleep. The findings from these studies were mixed. Cannabis was associated with a variety of impacts on sleep ranging from beneficial effects, such as reduced sleep-onset latency, to negative outcomes, such as reduced sleep duration and suppressed rapid eye movement oscillations. The chronology of the interaction of cannabis and sleep was unclear, although much of the current literature focus on factors that modulate how cannabis impairs sleep after initial use. Conclusion: There was sufficient evidence to suggest that cannabis use alters circadian rhythms, and hence, negatively impacts sleep. The current literature is largely from studies utilizing self-report measures of sleep; thus, objective measures of sleep are needed. In addition, although there were no empirical studies on the temporal relationship between cannabis use and sleep, the majority of the literature focused on characterizing sleep impairment after cannabis use.
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Background: Sleep is essential for wellbeing, yet sleep disturbance is a common problem linked to a wide range of health conditions. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide proposed to promote better sleep via potential interaction with the endocannabinoid system. Methods: This double-blind, randomized study on 103 adults compared the efficacy and tolerability of 8 weeks of daily supplemented PEA formulation (350 mg Levagen+TM) to a placebo. Sleep quality and quantity were measured using wrist actigraphy, a sleep diary and questionnaires. Results: At week 8, PEA supplementation reduced sleep onset latency, time to feel completely awake and improved cognition on waking. After 8 weeks, both groups improved their sleep quality and quantity scores similarly. There was no difference between groups at baseline or week 8 for sleep quantity or quality as measured from actigraphy or sleep diaries. Conclusion: These findings support PEA as a potential sleeping aid capable of reducing sleep onset time and improving cognition on waking. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12618001339246. Registered 9th August 2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375493&isReview=true
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Background: Limited evidence suggests that early cannabis use is associated with sleep problems. Research is needed to understand the developmental impact of early regular cannabis use on later adult sleep duration. Methods: In a sample of 1656 adult twins (56% female, Mean age = 25.79yrs), linear mixed effects models were used to analyze the influence of retrospectively assessed age of onset of regular cannabis use on adult sleep duration controlling for sex, depression, and current substance use. Twin analyses provided genetic and environmental variance estimates as well as insights into the association and potential casual relationships between these traits. Results: Earlier age of onset for regular cannabis use was significantly associated with shorter adult sleep duration on both weekdays (β = -0.13, 95% CI = [-0.23, -0.04]) and weekends (β = -0.18, 95% CI = [-0.27, -0.08]). Additive genetics significantly contributed to the onset of regular cannabis use (a2 = 76%, 95% CI = [68, 85]) and adult weekend sleep duration (a2 = 20%, 95% CI = [11, 32]). We found evidence of a significant genetic correlation (rA = -0.31, 95% CI = [-0.41, -0.15]) between these two traits and our best fitting model was consistent with early onset of regular cannabis use causing shorter adult weekend sleep duration (β = -0.11, 95% CI = [-0.18, -0.03]). Conclusions: Our results are consistent with the hypothesis that early onset of regular cannabis use may have a negative impact on adult sleep duration.
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Introduction: Insomnia in Major Depressive Disorder (MDD) is highly prevalent and associated with increased suffering and functional impairment. Effective, evidence-based treatments for insomnia in MDD are an unmet need in clinical practice. Areas covered: Herein, the authors provide a review of the clinical correlates, putative neurobiological mechanisms and treatment options for the management of insomnia in individuals with MDD. Expert opinion: Sleep disturbances in MDD should be recognized as at least one of the following: 1) a domain of depressive psychopathology; 2) a consequence of rhythm disruptions; 3) a manifestation of comorbidities of sleep disturbances; 4) a manifestation of the influence of sex hormones in the brain in MDD; 5) a general medical comorbidity; and 6) a side effect of antidepressant medications. Assessment of insomnia in clinical practices is routinely performed with the use of non- structured interviews. Other methods, such as standardized questionnaires and sleep diaries, along with complementary methods such as actigraphy, and polysomnography are more scarcely applied. Smartphones and personal devices offer a promising strategy with the use of passive, long-lasting, and ecologically valid assessments despite the lack of studies specifically targeting insomnia in individuals with MDD. New therapeutic approaches are essential, including novel targets such as orexins/hypocretin and the endocannabinoid system.
Chapter
The endogenous cannabinoid system is an important regulatory system involved in physiological homeostasis. Endocannabinoid signaling is known to modulate neural development, immune function, metabolism, synaptic plasticity, and emotional state. Accumulating evidence also implicates brain endocannabinoid signaling in the processing of natural and drug-induced reward states and dysregulated endocannabinoid signaling in the etiology of aberrant reward function and drug addiction. In this chapter, we discuss the influence of endocannabinoid signaling on the rewarding and motivational effects of natural rewards such as food, sex, and social interaction, as well as evidence demonstrating an endocannabinoid influence in the rewarding effects of abused drugs. The effects of long-term drug consumption on endocannabinoid signaling are discussed, along with evidence that the resultant dysregulation of endocannabinoid function contributes to various aspects of drug dependence and addiction including physical symptoms of drug withdrawal, increased stress responsivity, negative affective states, dysregulated synaptic plasticity, dysregulated extinction of drug-related memories, relapse to drug taking, and impaired cognitive function. Lastly, consideration is given to the role for dysregulated endocannabinoid signaling in pathological food reward and eating disorders.
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The endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are bioactive lipids implicated in numerous pathophysiological processes, such as inflammation, analgesia, mood disorders, food intake, and obesity. Classically, they exert their effects by activating two G protein-coupled receptors, the cannabinoid receptors 1 and 2. The actions of AEA and 2-AG are terminated by their hydrolysis by specific lipases into arachidonic acid and ethanolamine or glycerol, respectively. However, due to their arachidonoyl moiety, AEA and 2-AG can also be metabolized by enzymes of the eicosanoids pathway, such as cyclooxygenase-2 (COX-2), lipoxygenase, and cytochrome P450 enzymes. This oxidative metabolism is not merely a means to end the endocannabinoid signaling, but leads to the production of bioactive lipids in their own right that can exert a variety of actions. The COX-2-derived prostaglandin-ethanolamides and prostaglandin-glycerol esters are examples of such bioactive lipids, and add to the complexity of endocannabinoid signaling.
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In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.
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The brain reward system is critical for survival. The hedonic effects produced by eating, exercise and sexual activity provide important motivational effects that increase the likelihood of future engagement in these criti­ cal activities (that is, positive reinforcement). The reward system is also essential for important negative hedonic responses, in which aversive or unpleasant events (for example, sickness or bodily harm) increase the likeli­ hood of behaviours that will avoid or relieve these negative states (that is, negative reinforcement). Seminal discoveries demonstrating that the effects of marijuana (cannabis sativa) are mediated by canna­ binoid receptors in the brain propelled significant research initiatives that expanded our knowledge about the body's endogenous cannabinoid system (termed the endocannabinoid (eCB) system (ECS)), which is now acknowledged to have a prominent role in modulat­ ing brain reward function and maintaining emotional homeostasis. This Review examines the evidence for an eCB influence in the positive­reinforcing effects of natural rewards and drugs of abuse. In contrast to the initial pleasurable experience of rewarding stimuli, pro­ longed drug exposure contributes to aberrant synaptic plasticity, negative emotional states and impaired learn­ ing and memory processes that sustain compulsive drug consumption, which is characteristic of the addicted state. We explore the ECS signalling underlying these maladaptive processes and provide an overview of the existing literature regarding the genetic factors that are associated with the ECS to gain insight about the potential contribution of ECS signalling dysregulation to addiction disorders.
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Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual’s sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group.
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Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB(1) cannabinoid receptor (K(i) = 21.2 +/- 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB(2) receptor (K(i) > 3 microM).
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This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12months. We found increased levels of oleoylethanolamide in CSF (P=0.011) but not in serum (P=0.068) after 24h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-α (PPAR-α) with nanomolar potency. Exogenous PPAR-α agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation.
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The endocannabinoid 2-arachidonoylglycerol (2-AG) is a lipid mediator involved in various physiological processes. In response to neural activity, 2-AG is synthesized post-synaptically, then activates pre-synaptic cannabinoid CB1 receptors (CB1Rs) in a retrograde manner, resulting in transient and long-lasting reduction of neurotransmitter release. The signalling competence of 2-AG is tightly regulated by the balanced action between 'on demand' biosynthesis and degradation. We review recent research on monoacylglycerol lipase (MAGL), ABHD6 and ABHD12, three serine hydrolases that together account for approx. 99% of brain 2-AG hydrolase activity. MAGL is responsible for approx. 85% of 2-AG hydrolysis and colocalizes with CB1R in axon terminals. It is therefore ideally positioned to terminate 2-AG-CB1R signalling regardless of the source of this endocannabinoid. Its acute pharmacological inhibition leads to 2-AG accumulation and CB1R-mediated behavioural responses. Chronic MAGL inactivation results in 2-AG overload, desensitization of CB1R signalling and behavioural tolerance. ABHD6 accounts for approx. 4% of brain 2-AG hydrolase activity but in neurones it rivals MAGL in efficacy. Neuronal ABHD6 resides post-synaptically, often juxtaposed with CB1Rs, and its acute inhibition leads to activity-dependent accumulation of 2-AG. In cortical slices, selective ABHD6 blockade facilitates CB1R-dependent long-term synaptic depression. ABHD6 is therefore positioned to guard intracellular pools of 2-AG at the site of generation. ABHD12 is highly expressed in microglia and accounts for approx. 9% of total brain 2-AG hydrolysis. Mutations in ABHD12 gene are causally linked to a neurodegenerative disease called PHARC. Whether ABHD12 qualifies as a bona fide member to the endocannabinoid system remains to be established.
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Cannabinoids, the active ingredients in marijuana, have dramatic effects on various organ systems. They exert their effects through two receptor types: CB1, primarily located in the brain, and CB2, primarily located in the immune system. Vertebrates also produce their own cannabinoid-like substances called endocannabinoids, including anandamide and 2-arachidonoylglyceral. Interestingly, some effects of endocannabinoids could not be explained by the signals through either CB1 or CB2. Recently, the orphan G protein-coupled receptor 55 (GPR55) was proposed to be an atypical cannabinoid receptor. In this issue of Oncogene, two groups demonstrated that GPR55 is expressed in various cancer types in an aggressiveness-related manner, suggesting a novel cancer biomarker and a potential therapeutic target.
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GPR55 is an orphan G protein-coupled receptor that may be engaged by some lipid ligands such as lysophosphatidylinositol and cannabinoid-type compounds. Very little is known about its expression pattern and physio-pathological relevance, and its pharmacology and signaling are still rather controversial. Here we analyzed the expression and function of GPR55 in cancer cells. Our data show that GPR55 expression in human tumors from different origins correlates with their aggressiveness. Moreover, GPR55 promotes cancer cell proliferation, both in cell cultures and in xenografted mice, through the overactivation of the extracellular signal-regulated kinase cascade. These findings reveal the importance of GPR55 in human cancer, and suggest that it could constitute a new biomarker and therapeutic target in oncology.
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Considerable efforts have been made to characterize the pathways regulating the extracellular levels of the endocannabinoid anandamide. However, none of such pathways has been so argued as the existence of a carrier-mediated transport of anandamide across the membrane. Apart from the lack of molecular evidence for such a carrier, the main reasons of this controversy lie in the methodologies currently used to study anandamide cellular uptake. Furthermore, the main evidence in favor of the existence of an "anandamide transporter" relies on synthetic inhibitors of this process, the selectivity of which has been questioned. We used the cytosolic binding site for anandamide on TRPV1 channels as a biosensor to detect anandamide entry into cells, and exploited nanotechnologies to study anandamide membrane transport into intact TRPV1-overexpressing HEK-293 cells. Both fluorescence and digital holographic (DH) quantitative phase microscopy were used to study TRPV1 activation. Poly-epsilon-caprolactone nanoparticles (PCL-NPs) were used to incorporate anandamide, which could thus enter the cell and activate TRPV1 channels bypassing any possible specific protein(s) involved in the uptake process. We reasoned that in the absence of such protein(s), pharmacological tools previously shown to inhibit the "anandamide transporter" would affect in the same way the uptake of anandamide and PCL-NP-anandamide, and hence the activation of TRPV1. However, when masked into PCL-NPs, anandamide cellular uptake became much less sensitive to these agents, although it maintained the same pharmacokinetics and pharmacodynamics as that of "free" anandamide. We found here that several agents previously reported to inhibit anandamide cellular uptake lose their efficacy when anandamide is prevented from interacting directly with plasma membrane proteins, thus arguing in favor of the specificity of such agents for the putative "anandamide transporter", and of the existence of such mechanism.
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Marijuana extract, given in daily doses containing 70 to 210 mg delta-9-tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movements density with some tolerance developing to this effect. Stage 4 tendend to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders. Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.
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The physiologic characteristics of the sleep-wake states have been well defined and some of the chemical and neuron systems that participate in the cyclic generation and maintenance of these states have been identified. The actual dynamic process by which these systems interact to generate the basic sleep-wake cycle, however, remains a mystery.
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A series of experiments was conducted to determine the effects of orally administered 1-trans-Δ-9-tetrahydrocannabinol (THC) on both undisturbed and experimentally altered (by rapid eye movement [REM] deprivation) sleep patterns of young adult male volunteers. In the deprivation experiments, the effects of a semisynthetic Δ-6a-10-THC homologue, synhexl, were also studied. In the normative studies, 4 subjects received THC in doses ranging from 61 to 258 μg per kilogram shortly before sleep onset, while in the deprivation experiments 2 subjects received either THC (244 μg per kilogram and 259 μg per kilogram) or synhexl (733 μg per kilogram and 777 μg per kilogram) the morning after the second of 2 consecutive nights of REM deprivation. In both normative and deprivation experiments, all-night sleep recordings were taken during base-line, drug, and postdrug conditions. The results of both types of experiments were consistent in demonstrating increments in Stage 4 sleep and decrements in REM sleep. In the normative experiments, reduction in Stage 1 and time awake after sleep onset were observed at the highest dose level. Interpretation of these results and their relation to the effects of other psychoactive compounds upon sleep pattern are discussed.
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Rat brain cannabinoid receptor (CB-1) was stably transfected into the murine tumor line AtT-20 to study its coupling to inwardly rectifying potassium currents (Kir) and high voltage-activated calcium currents (ICa). In cells expressing CB-1 ("A-2" cells), cannabinoid agonist potently and stereospecifically activated Kir via a pertussis toxin-sensitive G protein. ICa in A-2 cells was sensitive to dihydropyridines and omega CTX MVIIC, less so to omega CgTX GVIA and insensitive to omega Aga IVa. In CB-1 expressing cells, cannabinoid agonist inhibited only the omega CTX MVIIC-sensitive component of ICa. Inhibition of Q-type ICa was voltage dependent and PTX sensitive, thus similar in character to the well-studied modulation of N-type ICa. An endogenous cannabinoid, anandamide, activated Kir and inhibited ICa as efficaciously as potent cannabinoid agonist. Immunocytochemical studies with antibodies specific for class A, B, C, D, and E voltage-dependent calcium channel alpha 1 subunits revealed that AtT-20 cells express each of these major classes of alpha 1 subunit.
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In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
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The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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A molecule isolated from the cerebrospinal fluid of sleep-deprived cats has been chemically characterized and identified as cis-9,10-octadecenoamide. Other fatty acid primary amides in addition to cis-9,10-octadecenoamide were identified as natural constituents of the cerebrospinal fluid of cat, rat, and human, indicating that these compounds compose a distinct family of brain lipids. Synthetic cis-9,10-octadecenoamide induced physiological sleep when injected into rats. Together, these results suggest that fatty acid primary amides may represent a previously unrecognized class of biological signaling molecules.
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