Cannabinoids and Sleep: Exploring Biological Mechanisms and Therapeutic Potentials.

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.

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson's Disease.

The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.

Development of indole-2-carbonyl piperazine urea derivatives as selective FAAH inhibitors for efficient treatment of depression and pain.

Fatty acid amide hydrolase (FAAH), aserinehydrolase with significant role in thehydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC50 = 0.12 µM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics.

A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18 µM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.

Endocannabinoid markers in autism spectrum disorder: A scoping review of human studies.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and patterns of restrictive and repetitive behavior. Although the neurological underpinnings of ASD remain elusive, the endocannabinoid system (ECS) may play a role in modulating social behavior in ASD. Preclinical studies have suggested that alterations in the ECS result in ASD-like phenotypes, but currently no reviews have examined ECS abnormalities in human studies. This scoping review investigated any evidence of ECS alterations in humans with ASD. A comprehensive literature search was conducted and five studies were eligible for review. Three studies reported a significant reduction of anandamide in ASD compared to controls. Other alterations included decreased 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide and elevated diacylglycerol lipase and monoacylglycerol lipase. Some discrepant findings were also noted, which included elevated or reduced CB2 receptor in three studies and elevated or reduced N-acyl phosphatidylethanolamine phospholipase D and fatty acid amide hydrolase in two studies. We conclude from this preliminary investigation that the ECS may be altered in humans with ASD. Potential limitations of the reviewed studies include medication use and psychiatric comorbidities. Further research, such as positron emission tomography studies, are necessary to fully understand the relationship between ECS markers and ASD.

The Effects of Repeated Morphine Treatment on the Endogenous Cannabinoid System in the Ventral Tegmental Area.

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.

Mini-review: The therapeutic role of cannabinoids in neuroHIV.

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-1-associated neurocognitive disorders (HAND). The endocannabinoid (eCB) system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential anti-inflammatory and neuroprotective properties of cannabinoids, including its potential therapeutic use in HIV-1 neuropathogenesis. In this review, we summarize what is currently known about the structural and functional changes of the eCB system under conditions of HAND. This will be followed by summarizing the current clinical and preclinical findings on the effects of cannabis use and cannabinoids in the context of HIV-1 infection, with specifically focusing on viral load, cognition, inflammation, and neuroprotection. Lastly, we present some potential future directions to better understand the involvement of the eCB system and the role that cannabis use and cannabinoids play in neuroHIV.

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons (Papio spp.).

Poor nutrition during pregnancy is a worldwide public health problem. Maternal nutrient reduction (MNR) is associated with maternal and fetal stress and a sex-dependent decrease in nonhuman primate (NHP) cognitive performance. Early life stress potentiates epileptogenesis in a sex-specific manner, and temporal lobe (TL) epilepsy is associated with neurocognitive disorders. The endogenous cannabinoid system (ECS) demonstrates remarkable developmental changes and plays a key role in aging-related diseases (e.g., dementia). Baboons have been studied as a natural model of epilepsy and express all ECS system components. We therefore evaluated baboon fetal temporal cortex ECS ontogenic and MNR-dependent changes. At 120 days gestational age (dGA) (term 185 days), maternal, fetal, and placental morphometry were similar between control and MNR pregnancies. MNR maternal weight gain was decreased compared with controls at 165 dGA independent of fetal sex. In male fetuses, expression of ECS synthesizing and degrading enzymes was gestational age-dependent, with the exception of fatty acid amide hydrolase (FAAH). MNR had a sex-specific effect on the protein expression of CB1R during development: CB1R protein expression was decreased in fetal temporal cortex of male fetuses at 120 and 140 dGA. Our data reveal that the MNR has sex-specific effects on temporal cortical expression of the ECS in baboon offspring and shows vulnerability of ECS in male fetuses during gestation.

Betacaryophyllene - A phytocannabinoid as potential therapeutic modality for human sepsis?

Sepsis is a clinical condition resulting from a dysregulated immune response to an infection that leads to organ dysfunction. Despite numerous efforts to optimize treatment, sepsis remains to be the main cause of death in most intensive care units. The endogenous cannabinoid system (ECS) plays an important role in inflammation. Cannabinoid receptor 2 (CB2R) activation is immunosuppressive, which might be beneficial during the hyper-inflammatory phase of sepsis. Beta-caryophyllene (BCP) is a non-psychoactive natural cannabinoid (phytocannabinoid) found in Cannabis sativa and in essential oils of spices and food plants, that acts as a selective agonist of CB2R. We propose BCP administration as novel treatment to reduce hyper-inflammation in human sepsis.

Monoacylglycerol lipase (MAGL) as a promising therapeutic target.

Monoacylglycerol lipase (MAGL) has been characterized as the main enzyme responsible for the inactivation of the most abundant brain endocannabinoid, 2-arachidonoylglycerol (2-AG). Besides this role, MAGL has progressively acquired a growing importance as an integrative metabolic hub that controls not only the in vivo levels of 2-AG but also of other monoacylglycerides and, indirectly, the levels of free fatty acids derived from their hydrolysis as well as other lipids with pro-inflammatory or pro-tumorigenic effects, coming from the further metabolism of fatty acids. All these functions have only started to be elucidated in the last years due to the progress made in the knowledge of the structure of MAGL and in the development of genetic and chemical tools. In this review we report the advances made in the field with a special focus on the last decade and how MAGL has become a promising therapeutic target for the treatment of several diseases that currently lack appropriate therapies.

Lifestyle causes of male infertility.

OBJECTIVE: To examine the potential effects of lifestyle factors on male reproductive health. Evidence of a global decline in human sperm quality over recent decades has been accumulating. Environmental, occupational, and modifiable lifestyle factors may contribute to this decline. This review focuses on key lifestyle factors that are associated with male infertility such as smoking cigarettes, alcohol intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, dietary practices, and coffee consumption. Other factors such as testicular heat stress, intense cycling training, lack of sleep and exposure to electromagnetic radiation from mobile phone use are briefly discussed. MATERIALS AND METHOD: A comprehensive literature search was performed to identify and synthesise all relevant information, mainly from within the last decade, on the major lifestyle factors associated with male infertility and semen quality. Database searches were limited to reports published in English only. A manual search of bibliographies of the reports retrieved was conducted to identify additional relevant articles. RESULTS: In all, 1012 articles were identified from the database search and after reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria. Of these, 30 reports were excluded as the full-text could not be retrieved and the abstract did not have relevant data. The remaining 74 reports were reviewed for data on association between a particular lifestyle factor and male infertility and were included in the present review. CONCLUSION: The major lifestyle factors discussed in the present review are amongst the multiple potential risk factors that could impair male fertility. However, their negative impact may well be mostly overcome by behaviour modification and better lifestyle choices. Greater awareness and recognition of the possible impact of these lifestyle factors are important amongst couples seeking conception.

Role of the endocannabinoid system in the control of mouse myometrium contractility during the menstrual cycle.

Cannabis and cannabinoids are known to affect female reproduction. However, the role of the endocannabinoid system in mouse uterine contractility in the dioestrus and oestrus phases has not been previously investigated. The present study aimed at filling this gap. Endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in mouse uterus at dioestrus and oestrus phases by liquid chromatography-mass spectrometry; quantitative reverse transcription-PCR and western blot were used to measured the expression of cannabinoid receptors and enzymes involved in the metabolism of endocannabinoids. Contractility was evaluated in vitro either on the spontaneous contractions or by stimulating the isolated uterus with exogenous spasmogens. The tissue concentrations of anandamide and 2-AG were reduced in the oestrus phase, compared to dioestrus. Uteri obtained in the dioestrus, but not oestrus, phase showed spontaneous phasic prostaglandin-mediated contractions that were reduced by ACEA (CB1 receptor agonist) and to a lower extent by JWH133 (CB2 receptor agonist). These inhibitory effects were counteracted by the corresponding selective antagonists. Neither ACEA nor JWH133 did affect the contractions induced by exogenous PGE2 in the uterus from the oestrus phase. The FAAH inhibitor JNJ1661010 and, to a lower extent, the MAGL inhibitor JZL184 also reduced spontaneous contractions. It is concluded that the endocannabinoid system undergoes to adaptive changes between the oestrus and dioestrus phases. CB1 and, to a lower extent, CB2 receptor activation results in selective inhibition of myometrial contractility, without un-specific relaxing effects on the smooth muscle. These results might be of interest for female marijuana smokers as well as for the design of novel tocolytic agents.

Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK.

AIM: To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS: We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS: The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited. CONCLUSION: These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system.

Papel del sistema cannabinoide endógeno en el intestino / Role of the endogenous cannabinoid system in the gut / Papel do sistema canabinoide endógeno no intestino

RESUMEN El sistema cannabinoide endógeno es un nuevo sistema de comunicación intercelular que constituye una pieza crucial en la regulación de la función intestinal. Se realizó una revisión bibliográfica con el objetivo de describir cómo el sistema cannabinoide endógeno modula la función intestinal. Se consultaron un total de 31 referencias bibliográficas entre libros, revistas, tesis doctorales y artículos en internet. Se encontró que los endocannabinoides son inmunomoduladores a nivel intestinal, que el sistema cannabinoide endógeno regula la composición de la microbiota intestinal y esta a su vez determina la concentración de los endocannabinoides, además tanto la secreción como la motilidad intestinal disminuyen por estimulación del sistema cannabinoide endógeno. Los receptores de cannabinoides, los endocannabinoides anandamida y 2-araquidonoilglirerol y las proteínas responsables de su síntesis y degradación están ampliamente distribuidos en el intestino en condiciones fisiológicas, aumentando su expresión en la enfermedad inflamatoria intestinal lo que le permite regular la función intestinal en ambas condiciones. El sistema cannabinoide endógeno tiene un enorme potencial terapéutico en la enfermedad inflamatoria intestinal debido a los efectos inmunosupresores, antiinflamatorios y analgésicos que posee.

ABSTRACT The endogenous cannabinoid system is a new intercellular communication system that constitutes a crucial piece in the regulation of intestinal function. A bibliographic review was carried out in order to describe how the endogenous cannabinoid system modulates intestinal function. A total of 31 bibliographic references were consulted between books, magazines, doctoral theses and articles on the internet. It was found that endocannabinoids are immunomodulatory at the intestinal level, that the endogenous cannabinoid system regulates the composition of the intestinal microbiota and this in turn determines the concentration of endocannabinoids, in addition both secretion and intestinal motility decrease by stimulation of the endogenous cannabinoid system. The cannabinoid receptors, the endocannabinoids anandamide and 2-arachidonoylglirerol, and the proteins responsible for their synthesis and degradation are widely distributed in the intestine under physiological conditions, increasing their expression in inflammatory bowel disease, which allows it to regulate intestinal function in both conditions. The endogenous cannabinoid system has enormous therapeutic potential in inflammatory bowel disease due to its immunosuppressive, anti-inflammatory and analgesic effects.

RESUMO O sistema canabinoide endógeno é umnovo sistema de comunicação intercelular que constitui uma peça crucial na regulação da função intestinal. Foi realizada uma revisão bibliográfica para descrever como o sistema canabinoide endógeno modula a função intestinal. Foram consultadas 31referências bibliográficas entre livros, revistas, teses de doutorado e artigosna internet. Verificou-se que os endocanabinoides são imunomoduladores em nível intestinal, que o sistema canabinoide endógeno regula a composição da microbiota intestinal e esta, por sua vez, determina a concentração de endocanabinoides, além da diminuição da secreção e da motilidade intestinal pela estimulação do sistema canabinoide endógeno. Os receptores canabinoides, os endocanabinoides anandamida e 2-araquidonoilglirerol e as proteínas responsáveis ​​por sua síntese e degradação estão amplamente distribuídos no intestino em condições fisiológicas, aumentando sua expressão em doenças inflamatórias intestinais que permitem regular a função intestinal em ambas as condições. O sistema canabinoide endógeno apresenta enorme potencial terapêutico na doença inflamatória intestinal devido aos seus efeitos imunossupressores, antiinflamatórios e analgésicos.

Differential role of cannabinoids in the pathogenesis of skin cancer.

AIM: Cannabinoids (CB) like ∆(9)-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. However, the use of cannabinoids for the treatment of malignant diseases is discussed controversially because of their immunomodulatory effects which can suppress anti-tumor immunity. Here we investigated the role of exogenous and endogenous cannabinoids in mouse skin cancer. MAIN METHODS: First we examined the effect of THC, which binds to CB receptors (CB1, CB2), on the growth of the mouse melanoma cell lines B16 and HCmel12 in vitro and in vivo in wild type (WT) and CB1/CB2-receptor deficient mice (Cnr1/2(-/-)). Next we evaluated the role of the endogenous cannabinoid system by studying the growth of chemically induced melanomas, fibrosarcoma and papillomas in WT and Cnr1/2(-/-) mice. KEY FINDINGS: THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment. Chemically induced skin tumors developed in a similar manner in Cnr1/2(-/-) mice when compared to WT mice. SIGNIFICANCE: Our results confirm the value of exogenous cannabinoids for the treatment of melanoma but do not support a role for the endogenous cannabinoid system in the pathogenesis of skin cancer.

Effects of CB1 receptor agonism and antagonism on behavioral fear and physiological stress responses in adult intact, ovariectomized, and estradiol-replaced female rats.

There is growing interest in the development of cannabis-based therapies for the treatment of fear and anxiety disorders. There are a few studies, but none in females, of the effects of the highly selective cannabinoid receptor type 1 (CB1) agonist, arachidonyl 2'-chlorethylamide (ACEA), on behavioral fear. In experiment 1 involving gonadally-intact females, ACEA (either 0.1 or 0.01 mg/kg) was without effect in the elevated plus maze (EPM), and the lower dose decreased anxiety in the open field test (OFT). AM251 increased anxiety in the EPM and decreased locomotor activity in the OFT. Twenty-four hours after fear conditioning, neither ACEA nor AM251 affected generalized fear or conditioned fear recall. AM251 and 0.1 mg/kg ACEA impaired, and 0.01 mg/kg ACEA enhanced, within-session fear extinction. AM251 increased plasma corticosterone concentrations after the fear extinction session, whereas ACEA was without effect. Based on evidence that estradiol may moderate the effects of CB1 receptor signaling in females, experiment 2 involved ovariectomized (OVX) rats provided with 10-µg 17ß-Estradiol and compared with OVX rats without hormone replacement (oil vehicle). Irrespective of hormone treatment, AM251 increased anxiety in the EPM, whereas ACEA (0.01 mg/kg) was without effect. Neither hormone nor drug altered anxiety in the OFT, but estradiol increased and AM251 decreased distance traveled. After fear conditioning, AM251 decreased generalized fear. Neither hormone nor drug had any effect on recall or extinction of conditioned fear, however, ACEA and AM251 increased fear-induced plasma corticosterone concentrations. Further, when results with intact rats were compared with those from OVX rats, gonadal status did not moderate the effects of either AM251 or ACEA, although OVX displayed greater anxiety and fear than did intact rats. Thus, the effects of CB1 receptor antagonism and agonism in adult female rats do not depend on ovarian estradiol.

Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract.

Fatty acid amide hydrolase (FAAH) is the enzyme crucially involved in the modulation of physiological processes mediated by anandamide (AEA), as well as other endocannabinoids and non-cannabinoid biolipids in the gastrointestinal (GI) tract. FAAH also plays a major role in the etiology and the course of GI diseases and the inhibition of the enzyme has recently become a potential target for their therapy. In this review we look at the pharmacology of FAAH and possible clinical application of FAAH inhibitors in the treatment of GI disorders. In particular, we focus on inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), whose symptoms include abdominal pain and motility disturbances. We also discuss why the inhibitor-based drugs may replace in future conventional therapies for IBD and IBS.

The cannabinoid-1 receptor inverse agonist taranabant reduces abdominal pain and increases intestinal transit in mice.

BACKGROUND: Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal (GI) disorder with abdominal pain and decreased motility. Current treatments of IBS-C are insufficient. The aim of this study was to evaluate the potential application of taranabant, a cannabinoid type 1 (CB1) inverse agonist using mouse models mimicking the symptoms of IBS-C. METHODS: Changes in intestinal contractile activity were studied in vitro, using isolated mouse ileum and colon and intracellular recordings. In vivo, whole gastrointestinal transit (WGT) and fecal pellet output (FPO) were measured under standard conditions and with pharmacologically delayed GI transit. The antinociceptive effect was evaluated in mustard oil- and acetic acid-induced models of visceral pain. Forced swimming and tail suspension tests were performed and locomotor activity was measured to evaluate potential central side effects. KEY RESULTS: In vitro, taranabant (10(-10) -10(-7) mol L(-1)) increased contractile responses in mouse ileum and blocked the effect of the CB agonist WIN 55,212-2. Taranabant had no effect on the amplitude of electrical field stimulation (EFS)-evoked junction potentials. In vivo, taranabant (0.1-3 mg kg(-1), i.p. and 3 mg kg(-1), p.o.) increased WGT and FPO in mice and reversed experimental constipation. The effect of taranabant was absent in CB1(-/-) mice. Taranabant significantly decreased the number of pain-related behaviors in animal models. At the doses tested, taranabant did not display mood-related adverse side effects typical for CB1 receptor inverse agonists. CONCLUSIONS & INFERENCES: Taranabant improved symptoms related to slow GI motility and abdominal pain and may become an attractive template in the development of novel therapeutics targeting IBS-C.

Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.

The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.

Research progress in role and mechanism of endogenous cannabinoid system in hepatic disease / 中国药学杂志

OBJECTIVE: To analyze recent studies on the role of the endocannabinoid system in liver disease and related mechanism. METHODS: Reading domestic and international documents in recent years, we concluded a comprehensive integrated about them. RESULTS: This paper reviews the important role of the endocannabinoid in the development of liver disease, which focuses on the prevention and protection of the endocannabinoid on viral hepatitis, alcoholic fatty liver disease, non-alcoholic fatty liver disease, cholestatic liver disease and liver ischemia-reperfusion injury and the development of hepatic fibrosis and hepatic encephalopathy. CONCLUSION: Endocannabinoid system plays an important role in the treatment of liver disease. But for its complex mechanism of action, we need further research.