The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice

The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.

Endocannabinoid system and periodontitis: mechanisms and therapeutic implications / Sistema endocanabinoide e periodontite: mecanismos e implicações terapêuticas

Introdução: A periodontite é um importante problema de saúde pública. Embora o princípio da terapia da periodontite esteja focado principalmente na remoção do biofilme dental e dos fatores associados, sua fisiopatologia registra diferentes eventos moleculares e inflamatórios relacionados ao sistema imunológico do hospedeiro, como a participação do sistema endocanabinoide. Objetivo: Esta revisão teve como objetivo explorar e elucidar os mecanismos e papéis do sistema endocanabinoide na fisiopatologia da periodontite e suas possibilidades para futuras terapias relacionadas. Material e método: Realizou-se uma busca eletrônica na plataforma PubMed por estudos envolvendo a ação do sistema endocanabinoide sobre a periodontite. Resultado: Dezenove estudos clínicos e pré-clínicos foram incluídos nesta revisão narrativa. Conclusão: Os receptores canabinoides tipo 1 e 2 são componentes integrais do sistema endocanabinoide e manifestam-se de várias formas nos tecidos periodontais. As ações e mecanismos através dos quais os receptores canabinoides são ativados em locais saudáveis ou inflamados continuam a ser o foco de investigações em curso. Além disso, os fitocanabinoides e canabinoides sintéticos apresentam potencial como tratamentos, com estudos pré-clínicos indicando benefícios na redução da inflamação e na facilitação da reparação dos tecidos.

Introduction: Periodontitis is a major public health problem. Although the principle of periodontitis therapy is mainly focused on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system, as the participation of the endocannabinoid system. Objective: This review aimed to explore and elucidate the mechanisms and roles of the endocannabinoid system on periodontitis physiopathology and its possibilities for future related therapies. Material and method: An electronic search was carried out on the PubMed platform for studies involving the action of the endocannabinoid system on periodontitis. Result: Nineteen clinical and preclinical studies were included in this narrative review. Conclusion: Cannabinoid receptors type 1 and 2 are integral components of the endocannabinoid system, manifesting in various forms in the periodontal tissues. The actions and mechanisms through which cannabinoid receptors are activated in healthy or inflamed sites remain the focus of ongoing investigations. Moreover, phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair

Cannabis and cannabinoids as an alternative remedy in metabolic syndrome

Abstract Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ9-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ9-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities

Progress on the application of positron emission tomography imaging of cannabinoid type 1 receptor in neuropsychiatric diseases / 浙江大学学报·医学版

Cannabinoid type 1 receptor (CB1R), as the major member of the endocannabinoid system, is among the most abundant receptors expressed in the central nervous system. CB1R is mainly located on the axon terminals of presynaptic neurons and participate in the modulation of neuronal excitability and synaptic plasticity, playing an important role in the pathogenesis of various neuropsychiatric diseases. In recent years, the consistent development of CB1R radioligands and the maturity of molecular imaging techniques, particularly positron emission tomography (PET) may help to visualize the expression and distribution of CB1R in central nervous system . At present, CB1R PET imaging can effectively evaluate the changes of CB1R levels in neuropsychiatric diseases such as Huntington's disease and schizophrenia, and its correlation with the disease severity, therefore providing new insights for the diagnosis and treatment of neuropsychiatric diseases. This article reviews the application of CB1R PET imaging in Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, post-traumatic stress disorder, cannabis use disorder and depression.

Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies

Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.

The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data

Objective: Schizophrenia is a multifactorial disorder. It is known that a combination of extensive multiple common alleles may be involved in its etiology, each contributing with a small to moderate effect, and, possibly, some rare alleles with a much larger effect size. We aimed to perform a systematic review of association studies between schizophrenia (and its subphenotypes) and polymorphisms in the CNR1 gene, which encodes cannabinoid receptors classically implicated in schizophrenia pathophysiology, as well as to present unpublished results of an association study in a Brazilian population. Methods: Two reviewers independently searched for eligible studies and extracted outcome data using a structured form. Papers were retrieved from PubMed and ISI Web of Knowledge using the search term schizophrenia in combination with CNR1 or CB1 or cannabinoid receptor. Twenty-four articles met our inclusion criteria. We additionally present data from a study of our own comparing 182 patients with schizophrenia and 244 healthy controls. Results: No consistent evidence is demonstrated. Conclusion: Some seemingly positive association studies stress the need for further investigations of the possible role of endocannabinoid genetics in schizophrenia.

Rimonabant improves metabolic parameters partially attributed to restoration of high voltage-activated Ca2+ channels in skeletal muscle in HFD-fed mice

Cannabinoid type 1 receptor (CB1R) inhibition tends to be one of the promising strategies for the treatment of obesity and other related metabolic disorders. Although CB1R inhibition may cause adverse psychiatric effects including depression and anxiety, the investigation of the role of peripheral CB1R on weight loss and related metabolic parameters are urgently needed. We first explored the effect of rimonabant, a selective CB1R antagonist/inverse agonist, on some metabolic parameters in high fat-diet (HFD)-induced obesity in mice. Then, real-time PCR and electrophysiology were used to explore the contribution of high voltage-activated Ca2+ channels (HVACCs), especially Cav1.1, on rimonabant's effect in skeletal muscle (SM) in HFD-induced obesity. Five-week HFD feeding caused body weight gain, and decreased glucose/insulin tolerance in mice compared to those in the regular diet group (P<0.05), which was restored by rimonabant treatment compared to the HFD group (P<0.05). Interestingly, HVACCs and Cav1.1 were decreased in soleus muscle cells in the HFD group compared to the control group. Daily treatment with rimonabant for 5 weeks was shown to counter such decrease (P<0.05). Collectively, our findings provided a novel understanding for peripheral CB1R's role in the modulation of body weight and glucose homeostasis and highlight peripheral CB1R as well as Cav1.1 in the SM as potential targets for obesity treatment.

Inibição do transito gastrintestinal por antipsicoticos: estudo experimental da clozapina

A eficácia da clozapina(CLZ)como um agente antipsicótico atípico foi reconhecida desde o início dos anos 1960, sendo ainda nos dias atuais a droga de escolha no tratamento de casos de esquizofrenia refratários a outros antipsicóticos. Dentre os efeitos adversos da CLZ, a constipaçãoé relatada com frequência, podendo progredir para obstruçãointestinal, necrose intestinal,sepse intrabdominale morte. O presente estudoavaliou o mecanismo de ação da CLZsobre a motilidade gastrintestinalatravés da análise da taxa de trânsito intestinal (TI) e da excreção de pelotas fecais em camundongos. Foram utilizados camundongos Swiss, machos, peso 25-30g, provenientes do Biotério Central da UFC e o projeto foi aprovado pela CEPA/UFC (Proc. No. 57/2014).As drogas utilizadas foram: CLZ (2,5; 5; 10; 20mg/kg), neostigmina (NEO, 1mg/kg i.p.), serotonina (5-HT, 10mg/kg v.o.), alilisitiocianato (AITC 10mg/kg v.o.), domperidona (DOM, 20mg/kg v.o.), L-NAME (80 mg/kg i.p.), naloxona (2mg/kg s.c.), glibenclamida (5mg/kg i.p.) e AM251 (1mg/kg i.p.).A administração oral de CLZ 10 e 20 mg/kgreduziusignificativamente(p<0,05) o transito gastrintestinal (TI) em relação ao veículoa partir desse resultado optou-se pela menor dose efetiva de CLZ sobre a função motora intestinal para as avaliações subsequentes...

Clozapine (CLZ)an atypicalantipsychotic agentrecognized for its efficacy since the early 1960s stillsnowadays the drug of choice in treating refractory schizophrenia cases to other antipsychotics. Among the adverse effects of CLZ, constipation, often reported, may progress to bowel obstruction, intestinal necrosis, intraabdominal sepsis and death. This study evaluated the mechanism of action of CLZ on gastrointestinal motility by analyzingthe intestinal transit rate (IT) and excretionof fecal pellets in mice. Animals usedwereSwiss males, weight 25-30g, from the UFC Central Animal Facility and the project approved by the CEPA / UFC (Proc. No. 57/2014). The drugs used were: CLZ (2.5, 5, 10, 20mg/kgp.o.), neostigmine (NEO 1mg /kg i.p.), serotonin (5-HT, 10mg/kg p.o.), alilisotiocianate(AITC 10mg/kg p.o.) , domperidone (DOM 20mg/kg p.o.), L-NAME (80 mg/kg i.p.), naloxone (2 mg/kg s.c.), glibenclamide (5 mg/kg i.p.) and AM251 (1 mg/kg i.p.). Oral administration of CLZ 10 and 20 mg/kg significantly (p <0.05) inhibited ITfrom the vehicle.Based on the results we decided forthe smallest effective dose of CLZ active on intestinal motor function(10mg/kg)for subsequent evaluations...

A spider derived peptide, PnPP-19, induces central antinociception mediated by opioid and cannabinoid systems

Background: Some peptides purified from the venom of the spider Phoneutria nigriventer have been identified as potential sources of drugs for pain treatment. In this study, we characterized the antinociceptive effect of the peptide PnPP-19 on the central nervous system and investigated the possible involvement of opioid and cannabinoid systems in its action mechanism. Methods: Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. All drugs were administered by the intracerebroventricular route.Results: PnPP-19 induced central antinociception in mice in the doses of 0.5 and 1 µg. The non-selective opioid receptor antagonist naloxone (2.5 and 5 µg), µ-opioid receptor antagonist clocinnamox (2 and 4 µg), δ-opioid receptor antagonist naltrindole (6 and 12 µg) and CB1 receptor antagonist AM251 (2 and 4 µg) partially inhibited the antinociceptive effect of PnPP-19 (1 µg). Additionally, the anandamide amidase inhibitor MAFP (0.2 µg), the anandamide uptake inhibitor VDM11 (4 µg) and the aminopeptidase inhibitor bestatin (20 µg) significantly enhanced the antinociception induced by a low dose of PnPP-19 (0.5 µg). In contrast, the κ-opioid receptor antagonist nor-binaltorphimine (10 µg and 20 µg) and the CB2 receptor antagonist AM630 (2 and 4 µg) do not appear to be involved in this effect. Conclusions: PnPP-19-induced central antinociception involves the activation of CB1 cannabinoid, µ- and δ-opioid receptors. Mobilization of endogenous opioids and cannabinoids might be required for the activation of those receptors, since inhibitors of endogenous substances potentiate the effect of PnPP-19. Our results contribute to elucidating the action of the peptide PnPP-19 in the antinociceptive pathway.(AU)

Progress in study on endocannabinoids and cannabinoid receptors in the treatment for neuropathic pain / 中南大学学报(医学版)

Endocannabinoids and cannabinoid receptors are expressed in various central pain modulation regions. They maintain in dynamic changes in the expression level and distribution under different pathological and physiological conditions. These changes possess advantage as well as disadvantage. Exogenous administration of endocannabinoids exerts analgesic effect in different pain models, which is mainly mediated by the cannabinoid CB1 and CB2 receptors. Inhibition of enzymes for degrading endocannabinoids in different pain models also shows analgesic effect due to the increased local levels of endocannabinoids.

Avaliação do papel do sistema canabidiol em um modelo de lesão renal por isquemia/reperfusão em animais / Evaluation of the role of the cannabidiol system in an animal model of ischemia/reperfusion kidney injury

RESUMO Objetivo: Investigar os efeitos da administração de canabidiol em um modelo de isquemia/reperfusão renal em animais. Métodos: Foi induzida uma lesão renal, por meio de 45 minutos de isquemia renal seguida por reperfusão. Administrou-se canabidiol (5mg/kg) imediatamente após a reperfusão. Resultados: A isquemia/reperfusão aumentou os níveis de interleucina 1 e fator de necrose tumoral, o que foi atenuado pelo tratamento com canabidiol. Além disso, o canabidiol foi capaz de diminuir o dano oxidativo de lipídios e proteínas, mas não os níveis de nitrito/nitrato. A lesão renal após isquemia/reperfusão pareceu ser independente da expressão dos receptores canabidiol-1 e canabidiol-2, já que não houve aumento significante desses receptores após a reperfusão. Conclusão: O tratamento com canabidiol teve um efeito protetor contra a inflamação e o dano oxidativo em um modelo de isquemia/reperfusão renal. Esses efeitos parecem não ocorrer via ativação dos receptores canabidiol-1/canabidiol-2.

ABSTRACT Objective: This work aimed to investigate the effects of the administration of cannabidiol in a kidney ischemia/reperfusion animal model. Methods: Kidney injury was induced by 45 minutes of renal ischemia followed by reperfusion. Cannabidiol (5mg/kg) was administered immediately after reperfusion. Results: Ischemia/reperfusion increased the IL-1 and TNF levels, and these levels were attenuated by cannabidiol treatment. Additionally, cannabidiol was able to decrease lipid and protein oxidative damage, but not the nitrite/nitrate levels. Kidney injury after ischemia/reperfusion seemed to be independent of the cannabidiol receptor 1 and cannabidiol receptor 2 (CB1 and CB2) expression levels, as there was no significant increase in these receptors after reperfusion. Conclusion: The cannabidiol treatment had a protective effect against inflammation and oxidative damage in the kidney ischemia/reperfusion model. These effects seemed to be independent of CB1/CB2 receptor activation.

Localization of cannabinoid receptor 1 (CB1) in submandibular and sublingual salivary glands of mice throughout postnatal development / Localización de los receptores cannabinoides 1 (CB1) en glándulas salivales submandibulares y sublinguales de ratones durante el desarrollo postnatal

In view of the fact that human marijuana users often show dry mouth symptom, the present study was attempted to examine the localization of CB1, which was originally identified in brain, in the submandibular and sublingual salivary glands of postnatal developing male mice by immunohistochemistry. In submandibular gland, CB1-immunoreactivity was positive in a majority of acinar cells in forms of granular appearance in their apical cytoplasm, while it was negative in the ducts at newborn stage. The immunoreactivity decreased in the acinar cells at P1W and no immunoreactivity was detected in the acinar cells at P3W and thereafter. The immunoreactivity was positive in ductal cells at P3W and it remained positive thereafter until P8W stage. The immunoreaction was distinct on the apical plasmalemma of the intercalated ductal cells, while it was distinct on the basal plasmalemma of the granular convoluted ductal cells. The enhanced immunostaining on the lateral plasmalemma of the granular ductal cells was discerned only on P6W. In sublingual gland, CB1-immunoreactivity was detected in the demilune acinar cells and ductal cells only on P4W. Furthermore, CB1-immunoreactivity was shown to occur in the salivary ganglionic neurons, suggesting the CB1-inhibitory action in the saliva secretion through the parasympathetic nervous transmission.

En vista de que los usuarios humanos de la marihuana a menudo presentan síntomas de sequedad oral, en el presente estudio se intentó examinar la localización de CB1, que se identificó originalmente en el cerebro, en las glándulas salivales submandibulares y sublinguales durante el desarrollo postnatal en ratones machos. En la glándula submandibular, la inmunoreactividad CB1 fue positiva en la mayoría de las células acinares de apariencia granular en su citoplasma apical, mientras que fue negativa en los conductos en la etapa de recién nacidos. La inmunorreactividad disminuyó en las células acinares en P1W y no se detectó inmunoreactividad en las células acinares en P3W. La inmunoreactividad fue positiva en las células ductales en P3W y se mantuvo positiva hasta la etapa P8W. La inmunorreacción se observó en el plasmalema apical de las células ductales intercaladas, mientras que fue distinta en el plasmalema basal de las células ductales contorneadas granulares. La inmunotinción mejorada en el plasmalema lateral de las células ductales granulares fue distingible sólo en P6W. En la glándula sublingual, se detectó inmunoreactividad CB1 en las células acinares y se observaron células ductales solamente en P4W. Además, se demostró que la inmunoreactividad CB1 se produce en las neuronas ganglionares salivales, lo que sugiere la acción CB1 inhibitoria en la secreción de saliva a través de la transmisión parasimpática nerviosa.

Lack of association of DRD3 and CNR1 polymorphisms with premenstrual dysphoric disorders

Premenstrual dysphoric disorder [PMDD] is a mood disorder characterized with physical and affective symptoms during the luteal phase of susceptible women. The aim of this study was to investigate the association of Dopamine D3 receptor [DRD3] polymorphism, and Cannabinoid receptor Type 1 [CNR1] polymorphism with PMDD. Fifty one participants with documented PMDD according to the DSM IV criteria and 51 healthy controls were included in this cross sectional study. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews. The genotyping of DRD3 receptor and Cannabinoid type 1 receptors were performed using Taqmanfluorogenic assay method. Distribution of DRD3 and CNR1 polymorphism was not different between patients and controls. These findings do not support a major role of DRD3, and CNR1 polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder

A Cannabinoid Receptor Agonist N-Arachidonoyl Dopamine Inhibits Adipocyte Differentiation in Human Mesenchymal Stem Cells

Endocannabinoids can affect multiple cellular targets, such as cannabinoid (CB) receptors, transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and peroxisome proliferator-activated receptor gamma (PPARgamma). The stimuli to induce adipocyte differentiation in hBM-MSCs increase the gene transcription of the CB1 receptor, TRPV1 and PPARgamma. In this study, the effects of three endocannabinoids, N-arachidonoyl ethanolamine (AEA), N-arachidonoyl dopamine (NADA) and 2-arachidonoyl glycerol (2-AG), on adipogenesis in hBM-MSCs were evaluated. The adipocyte differentiation was promoted by AEA whereas inhibited by NADA. No change was observed by the treatment of non-cytotoxic concentrations of 2-AG. The difference between AEA and NADA in the regulation of adipogenesis is associated with their effects on PPARgamma transactivation. AEA can directly activate PPARgamma. The effect of AEA on PPARgamma in hBM-MSCs may prevail over that on the CB1 receptor mediated signal transduction, giving rise to the AEA-induced promotion of adipogenesis. In contrast, NADA had no effect on the PPARgamma activity in the PPARgamma transactivation assay. The inhibitory effect of NADA on adipogenesis in hBM-MSCs was reversed not by capsazepine, a TRPV1 antagonist, but by rimonabant, a CB1 antagonist/inverse agonist. Rimonabant by itself promoted adipogenesis in hBM-MSCs, which may be interpreted as the result of the inverse agonism of the CB1 receptor. This result suggests that the constantly active CB1 receptor may contribute to suppress the adipocyte differentiation of hBM-MSCs. Therefore, the selective CB1 agonists that are unable to affect cellular PPARgamma activity inhibit adipogenesis in hBM-MSCs.

Sistema endocanabinoide y desarrollo de esteatosis hepática / A role for the endocannabinoid system in hepatic steatosis

The endocannabinoid system (SEC) is an important modulator of several metabolic functions. This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome. Liver steatosis of different origins constitutes a physiopathological condition where an altered hepatic SEC is observed. In this condition, there is an increased expression of RCB1 and/or higher endocannabinoid levels in different hepatic cells, which may exert an autocrine/paracrine hyperstimulation of RCB1/RCB2. Activation of RCB1 stimulate the expression of several hepatocyte lipogenic factors, thus leading to increased de novo fatty acids synthesis and consequently to an abnormal accumulation of triglycerides. The effect of RCB2 activity on hepatic function is still controversial because, on one side its stimulation has an interesting protective effect on alcoholic liver disease while, on the other, it may enhance the development of hepatic steatosis in experimental models of diet-induced obesity. In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.

Cannabinoid receptor 1 controls nerve growth in ectopic cyst in a rat endometriosis model / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate whether cannabinoid receptor 1 (CB1R) is involved in nerve growth in endometriosis-associated ectopic cyst.</p><p><b>METHODS</b>The effect of CB1R agonist and antagonist on the expression of pan-neuronal marker protein gene product (PGP) 9.5 in ectopic cyst was examined by immunofluorescence and Western blot in endometriosis model of 18 rats.</p><p><b>RESULTS</b>Immunofluorescence revealed that PGP 9.5 was expressed in the nerve fibers and was mainly distributed in the cyst hilum. Western blot revealed that the protein density of either PGP 9.5 (2 week: 0.38 ± 0.05; 4 week: 0.63 ± 0.03; 8 week: 0.80 ± 0.07, P < 0.01) or CB1R (2 week: 0.48 ± 0.04; 4 week: 0.68 ± 0.01; 8 week: 0.80 ± 0.03, P < 0.01) in the ectopic cyst increased with cyst size. In addition, compared to control group (0.75 ± 0.01), PGP 9.5 expression in the ectopic cyst was promoted by CB1R agonist ACPA (0.81 ± 0.01, P < 0.05), and inhibited by CB1R antagonist AM251 (0.67 ± 0.03, P < 0.01).</p><p><b>CONCLUSIONS</b>CB1R was involved in the nerve growth of ectopic cyst associated with endometriosis.</p>

Dependence Potential of the Synthetic Cannabinoids JWH-073, JWH-081, and JWH-210: In Vivo and In Vitro Approaches

Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as "Spice" and "Smoke". Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Delta9-tetrahydrocannabinol (Delta9-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Delta9-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.

role of endocannabinoids system in fatty liver disease and therapeutic potentials

Non-alcoholic fatty liver disease [NAFLD] is a major cause of liver morbidity and mortality with no proven effective therapy as of yet. Its prevalence is increasing globally in parallel with obesity and metabolic syndrome pandemic. The endocannabinoid [EC] system has been implicated in the pathogenesis of several diseases, including fatty liver diseases. This system refers to the cannabinoid receptors type 1 [CB1] and type 2 [CB2], with both their endogenous ligands and machinery dedicated to EC synthesis and degradation. There is accumulating evidence on the role CB1 as a key mediator of insulin resistance and liver lipogenesis in both animals and humans. On the other hand, CB2 receptors have been shown to promote inflammation with anti-fibrogenic properties. The pharmacological modulation of the EC system activity for the treatment of metabolic syndrome and NAFLD are promising yet premature. The initial limited success due to deleterious central nervous system side-effects are likely to be bypassed with the use of peripherally restricted drugs

Activation of cannabinoid CB1 receptors modulates evoked action potentials in rat retinal ganglion cells / 生理学报

Activation of cannabinoid CB1 receptors (CB1Rs) regulates a variety of physiological functions in the vertebrate retina through modulating various types of ion channels. The aim of the present study was to investigate the effects of this receptor on cell excitability of rat retinal ganglion cells (RGCs) in retinal slices using whole-cell patch-clamp techniques. The results showed that under current-clamped condition perfusing WIN55212-2 (WIN, 5 μmol/L), a CB1R agonist, did not significantly change the spontaneous firing frequency and resting membrane potential of RGCs. In the presence of cocktail synaptic blockers, including excitatory postsynaptic receptor blockers CNQX and D-APV, and inhibitory receptor blockers bicuculline and strychnine, perfusion of WIN (5 μmol/L) hardly changed the frequencies of evoked action potentials by a series of positive current injection (from +10 to +100 pA). Phase-plane plot analysis showed that both average threshold voltage for triggering action potential and delay time to reach threshold voltage were not affected by WIN. However, WIN significantly decreased +dV/dtmax and -dV/dtmax of action potentials, suggestive of reduced rising and descending velocities of action potentials. The effects of WIN were reversed by co-application of SR141716, a CB1R selective antagonist. Moreover, WIN did not influence resting membrane potential of RGCs with synaptic inputs being blocked. These results suggest that activation of CB1Rs may regulate intrinsic excitability of rat RGCs through modulating evoked action potentials.

Functional activity of the cannabinoid 1 receptor is not affected by opioid antagonists in the rat brain / 대한마취과학회지

BACKGROUND: WIN55212-2 is a synthetic cannabinoid agonist and selective to cannabinoid 1 (CB1) receptors, which are distributed mainly in the central nervous system. Opioid receptors and CB1 receptors have several similarities in terms of their intracellular signal transduction mechanisms, distributions, and pharmacological action. Several studies have therefore sought to describe the functional interactions between opioids and cannabinoids at the cellular and behavioral levels. The present study investigated agonist-stimulated [35S]GTPgammaS binding by WIN55212-2 in rat brain membranes and determined the antagonism by selective opioid antagonists at the level of receptor-ligand interaction and intracellular signal transduction. METHODS: Sprague-Dawley rats (male, n = 20) were euthanized for the preparation of brain membranes. In agonist-stimulated [35S]GTPgammaS binding by WIN55212-2, the values of EC50 and maximum stimulation (% over basal) were determined in the absence or presence of the micro, kappa and delta opioid receptor antagonists naloxone (20 nM), norbinaltorphimine (3 nM), and naltrindole (3 nM), respectively. Ke values for opioid antagonist inhibition in the absence or presence of each opioid receptor antagonist were calculated using the following equation: [nanomolar antagonist] / (dose ratio of EC50 - 1). RESULTS: In WIN55212-2-stimulated [35S]GTPgammaS binding in the rat brain membranes, the values of EC50 and maximum stimulation (% over basal) were 154 +/- 39.5 nM and 27.6 +/- 5.3% over basal, respectively. Addition of selective opioid antagonists did not produce a significant rightward shift in the WIN55212-2 concentration-response curve, and Ke values were not applicable. CONCLUSIONS: Our results suggest that the functional activity of WIN55212-2-stimulated [35S]GTPgammaS binding was not affected by opioid antagonists in the rat brain membranes. Although the exact mechanism remains unclear, our results may partially elucidate their actions.