The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops in...The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.展开更多
Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports....Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.展开更多
Objective In recent years,abnormal changes in the endocannabinoid system have been found in schizophrenia. The superior temporal gyrus（STG）is strongly implicated in the pathophysiology of schizophrenia,particularly ...Objective In recent years,abnormal changes in the endocannabinoid system have been found in schizophrenia. The superior temporal gyrus（STG）is strongly implicated in the pathophysiology of schizophrenia,particularly with regards to auditory hallucinations.In this study,we investigated the binding density of cannabinoid CB1 receptors in the STG of schizophrenia patients compared to control subjects.Methods Quantitative autoradiography was used to investigate the binding densities of[^3H]SR141716A（a selective antagonist）and[^3H]CP-55940（an agonist）to the CB1 receptors in the STG.Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre（Australia）.Results Contrasting to previous findings in the alterations of CB1 receptor densities in the prefrontal,anterior and posterior cingulate cortex of schizophrenia,which were suggested to be associated to impairment of cognition function,no significant difference was found between the schizophrenia and control cases in both[^3H]SR141716A and[^3H]CP-55940 binding. Conclusion We suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease.展开更多
The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive un...The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.展开更多
Sulfur dioxide（SO_2） pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction.However,there are currently no effective medications targeting the...Sulfur dioxide（SO_2） pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction.However,there are currently no effective medications targeting the harmful outcomes from chemical inhalation.Endocannabinoids（eCBs） are involved in neuronal protection against inflammation-induced neuronal injury.The 2-arachidonoylglycerol（2-AG）,the most abundant eCBs and a full agonist for cannabinoid receptors（CB1 and CB2）,is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.Here,we indicated that endogenous 2-AG protected against neuroinflammation in response to SO_2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines,including tumor necrosis factor alpha（TNF-a）,interleukin（IL）-1β,and inducible nitric oxide synthase（iNOS）.In addition,endogenous 2-AG prevented cerebral vasculature dysfunction following SO_2 inhalation by inhibiting endothelin 1（ET-1）,vascular cell adhesion molecule-1（VCAM-1） and intercellular adhesion molecule 1（ICAM-1） expression,elevating endothelial nitric oxide synthase（eNOS） level,and restoring the imbalance between thromboxane A2（TXA2） and prostaglandin 12（PGI2）.In addition,the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO_2 inhalation.展开更多
This study examined endogenous carmabinoid （ECB）-anandamide （AEA） and its cannabinoid receptors （CBR） in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pa...This study examined endogenous carmabinoid （ECB）-anandamide （AEA） and its cannabinoid receptors （CBR） in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography （HPLC） was employed to determine the concentration of AEA in the plasma of mice. Immunofluo-rescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 （P〈0.05）. The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were （0.37±0.07） and （5.67±1.34） ng/mL （P〈0.05）. It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.展开更多
BACKGROUND Antagonists of cannabinoid type 1 receptor(CB1)have been shown to promote body weight loss and improve insulin sensitivity.Cannabinoids decrease adiponectin,and CB1 blocker increase adiponectin.However,the ...BACKGROUND Antagonists of cannabinoid type 1 receptor(CB1)have been shown to promote body weight loss and improve insulin sensitivity.Cannabinoids decrease adiponectin,and CB1 blocker increase adiponectin.However,the mediators of CB1 actions are not well defined.AIM To investigate whether the beneficial effects of CB1 inhibition are,at least in part,mediated by adiponectin.METHODS We compared metabolic and inflammatory phenotypes of wild-type(WT)mice,CB1-null(CB1^(-/-))and CB1/adiponectin double-knockout(DKO)mice.We assessed the insulin sensitivity using insulin tolerance test and glucose tolerance test,and inflammation using flow cytometry analysis of macrophages.RESULTS CB1^(-/-)mice exhibited significantly reduced body weight and fat mass when compared to WT mice.While no significance was found in total daily food intake and locomotor activity,CB1^(-/-)mice showed increased energy expenditure,enhanced thermogenesis in brown adipose tissue(BAT),and improved insulin sensitivity compared to WT mice.DKO showed no difference in body weight,adiposity,nor insulin sensitivity;only showed a modestly elevated thermogenesis in BAT compared to CB1^(-/-)mice.The metabolic phenotype of DKO is largely similar to CB1^(-/-)mice,suggesting that adiponectin is not a key mediator of the metabolic effects of CB1.Interestingly,CB1^(-/-)mice showed reduced pro-inflammatory macrophage polarization in both peritoneal macrophages and adipose tissue macrophages compared to WT mice;in contrast,DKO mice exhibited increased pro-inflammatory macrophage polarization in these macrophages compared to CB1^(-/-)mice,suggesting that adiponectin is an important mediator of the inflammatory effect of CB1.CONCLUSION Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms:CB1 regulates energy metabolism in an adiponectin-independent manner,and inflammation in an adiponectin-dependent manner.The differential effects of adiponectin on CB1-mediated metabolic and inflammatory functions should be taken into consideration in CB1 antagonist utilization.展开更多
Background: Cannabinoid receptor subtype 1 (CB1) has a relationship to the proliferation of various cells including malignant tumoral cells. We investigated and compared the expression of CB1 in benign and malignant h...Background: Cannabinoid receptor subtype 1 (CB1) has a relationship to the proliferation of various cells including malignant tumoral cells. We investigated and compared the expression of CB1 in benign and malignant human prostate tissues and in benign and malignant human prostate cell lines, as well as its function for the proliferation of human prostate cancer cells. Methods: Real-time quantitative PCR was performed to compare its expressions in human prostate tissues (normal, benign hyperplasia, and cancer) and prostate cell lines (3 normal and 3 malignant). For localization of CB1, immunofluorescent staining with rabbit anti-CB1 polyclonal antibodies and tetramethyl isothiocyanate (TRITC)-labeled swine anti-rabbit immunoglobulin (DAKO) were used under fluorescence microscope. To further analyze whether cell death was induced by anandamide (non-selective agonist for CB1/CB2) via a receptor dependent mechanism, the viability of DU145 cells, which is known as androgen-insensitive prostate cancer cell, was measured using MTT assay. Results: CB1mRNA was found to be expressed in the all 3 human prostate tissues, however, CB1 protein was expressed in BPH and low grade malignant PC tissues, but not in high grade malignant PC tissues. CB1 as for cell lines, the expression of CB1 was low in malignant cell lines except for DU145. Anandamide elicited cell death, which was significantly inhibited by AM251 (selective antagonist for CB1), indicating that cell death induced by anandamide in DU145 cells was mediated by CB1. Anandamide time-dependently elicits up-regulation of CB1 in DU145 cells. Conclusions: CB1 may be an inhibitory regulator of androgen-insensitive human prostate cancer epithelial cell growth.展开更多
Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not...Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects CB2 expression and if activation of CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in hPDL cells. Methods: The hPDL cells were obtained from extracted teeth of periodontally healthy subjects. CB2 expression in hPDL cells exposed to LPS was deter- mined by quantitative real-time PCR analysis. Then, the cells were incubated with or without CB2-specific agonist HU-308 before further stimulation with LPS. In some experiments, the cells were pre-treated with CB2-specific antagonist SR144528. The production of pro-inflammatory cytokines interleukin-1 beta (IL- 1β), interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α) was assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of osteoclastogenic genes osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) was examined using quantitative real-time PCR analysis. Results: CB2 expression in hPDL cells was markedly enhanced by LPS. HU-308 significantly suppressed the production of IL-1β, IL-6 and TNF-α exposed to LPS, whereas SR144528 attenuated this effect. The OPG/RANKL ratio decreased when exposed to LPS, furthermore increased significantly with the addition of HU-308 and finally decreased markedly after pretreatment with SR144528. Conclusion: Our study demonstrated that activation of CB2 had anti-inflammatory and anti-resorptive effects on LPS-stimulated hPDL cells. These findings suggest that activation of CB2 might be an effective therapeutic strategy for the treatment of inflammation and alveolar bone resorption in periodontitis.展开更多
Background Endocannabinoids acting via cannabinoid receptor 1(CB1R)can elicit increased intestinal permeability(a condition also called‘leaky gut’).Alcohol binge can adversely affect digestive functions,including in...Background Endocannabinoids acting via cannabinoid receptor 1(CB1R)can elicit increased intestinal permeability(a condition also called‘leaky gut’).Alcohol binge can adversely affect digestive functions,including intestinal permeability;however,the underlying mechanisms remain incompletely understood.The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.Methods We developed intestinal epithelial-specific CB1R knockout(CB1IEC−/−)mice and evaluated the in vivo contribution of gut CB1R in alcohol binge-induced intestinal permeability.Results Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability.Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain.Additionally,a peripheral CB1R antagonist,(S)-MRI-1891(INV-202/monlunabant),exhibited comparable binding affinity to CB1R in brain homogenates.An acute oral administration of(S)-MRI-1891(3 mg/kg)reduced alcohol binge-induced intestinal permeability in littermate control CB1f/f(CB1 floxed/floxed)mice but had no effect in CB1IEC−/−mice,underscoring the role of intestinal CB1R in this phenomenon.Mechanistically,we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length.In addition,targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process,with subsequent upregulation of tight junction proteins and increased villi length,thus improving gut barrier function.Despite the effects on intestinal permeability,deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.Conclusion Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.展开更多
Background Vascular hyporeactivity, which occurs in the terminal stage of hemorrhagic shock, is believed to be critical for treating hemorrhagic shock. The present study was designed to examine whether the CB1 cannabi...Background Vascular hyporeactivity, which occurs in the terminal stage of hemorrhagic shock, is believed to be critical for treating hemorrhagic shock. The present study was designed to examine whether the CB1 cannabinoid receptor （CB1 R） was involved in the development of vascular hyporeactivity in rats suffering from hemorrhagic shock. Methods Sixteen animals were randomly divided into two groups （n=8 in each group）： sham-operated （Sham） and hemorrhagic shock （HS） groups. Hemorrhagic shock was induced by bleeding. The mean arterial pressure （MAP） was reduced to and stabilized at （25±5） mmHg for 2 hours. The vascular reactivity was determined by the response of MAP to norepinephrine （NE）. In later experiments another twelve animals were used in which the changes of CB1R mRNA and protein in aorta and superior mesenteric artery （SMA） were analyzed by RT-PCR and Western blotting. In addition, we investigated the effects of a CB1R antagonist on the vascular hyporeactivity and survival rates in rats with hemorrhagic shock. Survival rates were analyzed by the Fisher＇s exact probability test. The MAP response was analyzed by one-way analysis of variance （ANOVA）. Results Vascular hyporeactivity developed in all animals suffering from hemorrhagic shock. The expression of CBIR mRNA and protein in aorta and 2-3 branches of the SMA were significantly increased in the HS group after the development of vascular hyporeactivity when compared to those in Sham group. When SR141716A or AM251 was administered, the MAP response to NE was （41.75±4.08） mmHg or （44.78±1.80） mmHg respectively, which was higher than that in saline groups with （4.31±0.36） mmHg （P 〈0.01）. We also showed an increased 4-hour survival rate in the SR141716A or AM251-treated group with 20% or 30%, but with a statistically significant difference present between the AM251-treated and saline groups （P 〈0.05）. Conclusions CBIR is involved in vascular hyporeactivity resulting from hemorrhagic shock in rats, and CB1R antagonist may be useful in treating patients with traumatic, hemorrhagic shock who need field-rescue or initial treatment.展开更多
Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK）...Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.展开更多
Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice...Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan.The nociceptive threshold was measured by von Frey filaments test.Tingenone was administered orally 60 min before carrageenan injection.To evaluate the involvement of CB2 receptor,endocannabinoids,and microglia,AM630(a CB2 receptor antagonist),MAFP(an inhibitor of an enzyme that hydrolyses endocannabinoids),and minocycline(a microglial inhibitor)were given intrathecally 20 min before tingenone administration.In addition,an immunofluorescence assay was used to evaluate CB2 receptor and CD11 B(a microglial marker)expression in the spinal cord dorsal horn.Results:Tingenone significantly reduced carrageenan-induced hyperalgesia,which was reversed by pretreatment with AM630.MAFP and minocycline potentiated and prolonged the tingenoneinduced antinociception.CD11 B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone,which was reduced by AM630,MAFP,and minocycline.Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.展开更多
The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regul...The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases.Here,we investigated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.展开更多
A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, w...A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.展开更多
Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals ...Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique.The CB1R antagonist rimonabant(1 or 3 mg/kg,i.p.)was administered either at one hour prior to the sample phase for acquisition,or immediately after the sample phase for consolidation,or at one hour before the test phase for retrieval of NOR memory.For the reconsolidation task,rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition,consolidation,and retrieval,but it did not affect the reconsolidation of NOR memory.Rimonabant administration did not affect acquisition,consolidation,and reconsolidation;however,it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings,along with our previous report,would seem to suggest that RSD may affect different phases of recognition memory based on its duration.Importantly,it seems that the CB1R may,at least in part,be involved in the adverse effects of chronic RSD on the retrieval,but not in the acquisition,consolidation,and reconsolidation,of NOR memory.展开更多
Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and ...Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.展开更多
基金supported by the National Natural Science Foundation of China(32300851)Zhejiang Provincial Natural Science Foundation(LQ24h310008).
文摘The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.
基金supported by a grant from Army Medical Research Program of China(No.08G168)
文摘Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.
文摘Objective In recent years,abnormal changes in the endocannabinoid system have been found in schizophrenia. The superior temporal gyrus（STG）is strongly implicated in the pathophysiology of schizophrenia,particularly with regards to auditory hallucinations.In this study,we investigated the binding density of cannabinoid CB1 receptors in the STG of schizophrenia patients compared to control subjects.Methods Quantitative autoradiography was used to investigate the binding densities of[^3H]SR141716A（a selective antagonist）and[^3H]CP-55940（an agonist）to the CB1 receptors in the STG.Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre（Australia）.Results Contrasting to previous findings in the alterations of CB1 receptor densities in the prefrontal,anterior and posterior cingulate cortex of schizophrenia,which were suggested to be associated to impairment of cognition function,no significant difference was found between the schizophrenia and control cases in both[^3H]SR141716A and[^3H]CP-55940 binding. Conclusion We suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease.
基金This work was supported by the National Natural Science Foundation of China(32271056,81671081,and 81701095)University Science and Technology Fund Planning Projects(2022XC002 and 2019XB006).
文摘The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
基金supported by the National Science Foundation of China(Nos.91543203,21477070,21377076,21307079)the Research Project Supported by Shanxi Scholarship Council of China(No.2015-006)
文摘Sulfur dioxide（SO_2） pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction.However,there are currently no effective medications targeting the harmful outcomes from chemical inhalation.Endocannabinoids（eCBs） are involved in neuronal protection against inflammation-induced neuronal injury.The 2-arachidonoylglycerol（2-AG）,the most abundant eCBs and a full agonist for cannabinoid receptors（CB1 and CB2）,is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.Here,we indicated that endogenous 2-AG protected against neuroinflammation in response to SO_2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines,including tumor necrosis factor alpha（TNF-a）,interleukin（IL）-1β,and inducible nitric oxide synthase（iNOS）.In addition,endogenous 2-AG prevented cerebral vasculature dysfunction following SO_2 inhalation by inhibiting endothelin 1（ET-1）,vascular cell adhesion molecule-1（VCAM-1） and intercellular adhesion molecule 1（ICAM-1） expression,elevating endothelial nitric oxide synthase（eNOS） level,and restoring the imbalance between thromboxane A2（TXA2） and prostaglandin 12（PGI2）.In addition,the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO_2 inhalation.
基金supported by a grant from the National Natural Sciences Foundation of China (No.30571627)
文摘This study examined endogenous carmabinoid （ECB）-anandamide （AEA） and its cannabinoid receptors （CBR） in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography （HPLC） was employed to determine the concentration of AEA in the plasma of mice. Immunofluo-rescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 （P〈0.05）. The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were （0.37±0.07） and （5.67±1.34） ng/mL （P〈0.05）. It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.
基金Supported by the NIH,No.DK118334 and No.AG064869and the BrightFocus,No.A2019630S(to Sun Y).
文摘BACKGROUND Antagonists of cannabinoid type 1 receptor(CB1)have been shown to promote body weight loss and improve insulin sensitivity.Cannabinoids decrease adiponectin,and CB1 blocker increase adiponectin.However,the mediators of CB1 actions are not well defined.AIM To investigate whether the beneficial effects of CB1 inhibition are,at least in part,mediated by adiponectin.METHODS We compared metabolic and inflammatory phenotypes of wild-type(WT)mice,CB1-null(CB1^(-/-))and CB1/adiponectin double-knockout(DKO)mice.We assessed the insulin sensitivity using insulin tolerance test and glucose tolerance test,and inflammation using flow cytometry analysis of macrophages.RESULTS CB1^(-/-)mice exhibited significantly reduced body weight and fat mass when compared to WT mice.While no significance was found in total daily food intake and locomotor activity,CB1^(-/-)mice showed increased energy expenditure,enhanced thermogenesis in brown adipose tissue(BAT),and improved insulin sensitivity compared to WT mice.DKO showed no difference in body weight,adiposity,nor insulin sensitivity;only showed a modestly elevated thermogenesis in BAT compared to CB1^(-/-)mice.The metabolic phenotype of DKO is largely similar to CB1^(-/-)mice,suggesting that adiponectin is not a key mediator of the metabolic effects of CB1.Interestingly,CB1^(-/-)mice showed reduced pro-inflammatory macrophage polarization in both peritoneal macrophages and adipose tissue macrophages compared to WT mice;in contrast,DKO mice exhibited increased pro-inflammatory macrophage polarization in these macrophages compared to CB1^(-/-)mice,suggesting that adiponectin is an important mediator of the inflammatory effect of CB1.CONCLUSION Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms:CB1 regulates energy metabolism in an adiponectin-independent manner,and inflammation in an adiponectin-dependent manner.The differential effects of adiponectin on CB1-mediated metabolic and inflammatory functions should be taken into consideration in CB1 antagonist utilization.
文摘Background: Cannabinoid receptor subtype 1 (CB1) has a relationship to the proliferation of various cells including malignant tumoral cells. We investigated and compared the expression of CB1 in benign and malignant human prostate tissues and in benign and malignant human prostate cell lines, as well as its function for the proliferation of human prostate cancer cells. Methods: Real-time quantitative PCR was performed to compare its expressions in human prostate tissues (normal, benign hyperplasia, and cancer) and prostate cell lines (3 normal and 3 malignant). For localization of CB1, immunofluorescent staining with rabbit anti-CB1 polyclonal antibodies and tetramethyl isothiocyanate (TRITC)-labeled swine anti-rabbit immunoglobulin (DAKO) were used under fluorescence microscope. To further analyze whether cell death was induced by anandamide (non-selective agonist for CB1/CB2) via a receptor dependent mechanism, the viability of DU145 cells, which is known as androgen-insensitive prostate cancer cell, was measured using MTT assay. Results: CB1mRNA was found to be expressed in the all 3 human prostate tissues, however, CB1 protein was expressed in BPH and low grade malignant PC tissues, but not in high grade malignant PC tissues. CB1 as for cell lines, the expression of CB1 was low in malignant cell lines except for DU145. Anandamide elicited cell death, which was significantly inhibited by AM251 (selective antagonist for CB1), indicating that cell death induced by anandamide in DU145 cells was mediated by CB1. Anandamide time-dependently elicits up-regulation of CB1 in DU145 cells. Conclusions: CB1 may be an inhibitory regulator of androgen-insensitive human prostate cancer epithelial cell growth.
文摘Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects CB2 expression and if activation of CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in hPDL cells. Methods: The hPDL cells were obtained from extracted teeth of periodontally healthy subjects. CB2 expression in hPDL cells exposed to LPS was deter- mined by quantitative real-time PCR analysis. Then, the cells were incubated with or without CB2-specific agonist HU-308 before further stimulation with LPS. In some experiments, the cells were pre-treated with CB2-specific antagonist SR144528. The production of pro-inflammatory cytokines interleukin-1 beta (IL- 1β), interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α) was assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of osteoclastogenic genes osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) was examined using quantitative real-time PCR analysis. Results: CB2 expression in hPDL cells was markedly enhanced by LPS. HU-308 significantly suppressed the production of IL-1β, IL-6 and TNF-α exposed to LPS, whereas SR144528 attenuated this effect. The OPG/RANKL ratio decreased when exposed to LPS, furthermore increased significantly with the addition of HU-308 and finally decreased markedly after pretreatment with SR144528. Conclusion: Our study demonstrated that activation of CB2 had anti-inflammatory and anti-resorptive effects on LPS-stimulated hPDL cells. These findings suggest that activation of CB2 might be an effective therapeutic strategy for the treatment of inflammation and alveolar bone resorption in periodontitis.
基金supported by the intramural programme of NIAAA,NIH(AA00350 to GK,AA000369 and AA000368 to BG)supported by Grant PD-139012 of the National Research,Development and Innovation Office and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.
文摘Background Endocannabinoids acting via cannabinoid receptor 1(CB1R)can elicit increased intestinal permeability(a condition also called‘leaky gut’).Alcohol binge can adversely affect digestive functions,including intestinal permeability;however,the underlying mechanisms remain incompletely understood.The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.Methods We developed intestinal epithelial-specific CB1R knockout(CB1IEC−/−)mice and evaluated the in vivo contribution of gut CB1R in alcohol binge-induced intestinal permeability.Results Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability.Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain.Additionally,a peripheral CB1R antagonist,(S)-MRI-1891(INV-202/monlunabant),exhibited comparable binding affinity to CB1R in brain homogenates.An acute oral administration of(S)-MRI-1891(3 mg/kg)reduced alcohol binge-induced intestinal permeability in littermate control CB1f/f(CB1 floxed/floxed)mice but had no effect in CB1IEC−/−mice,underscoring the role of intestinal CB1R in this phenomenon.Mechanistically,we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length.In addition,targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process,with subsequent upregulation of tight junction proteins and increased villi length,thus improving gut barrier function.Despite the effects on intestinal permeability,deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.Conclusion Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.
基金This work was supported by the grants from the National Natural Science Foundation of China （No. 30471675, No. 30672041 and No. 30725039）, National Natural Science Foundation of Shaanxi Province （No. 2004K17-G15） and National Natural Science Foundation of PLA （No. 06G086）.
文摘Background Vascular hyporeactivity, which occurs in the terminal stage of hemorrhagic shock, is believed to be critical for treating hemorrhagic shock. The present study was designed to examine whether the CB1 cannabinoid receptor （CB1 R） was involved in the development of vascular hyporeactivity in rats suffering from hemorrhagic shock. Methods Sixteen animals were randomly divided into two groups （n=8 in each group）： sham-operated （Sham） and hemorrhagic shock （HS） groups. Hemorrhagic shock was induced by bleeding. The mean arterial pressure （MAP） was reduced to and stabilized at （25±5） mmHg for 2 hours. The vascular reactivity was determined by the response of MAP to norepinephrine （NE）. In later experiments another twelve animals were used in which the changes of CB1R mRNA and protein in aorta and superior mesenteric artery （SMA） were analyzed by RT-PCR and Western blotting. In addition, we investigated the effects of a CB1R antagonist on the vascular hyporeactivity and survival rates in rats with hemorrhagic shock. Survival rates were analyzed by the Fisher＇s exact probability test. The MAP response was analyzed by one-way analysis of variance （ANOVA）. Results Vascular hyporeactivity developed in all animals suffering from hemorrhagic shock. The expression of CBIR mRNA and protein in aorta and 2-3 branches of the SMA were significantly increased in the HS group after the development of vascular hyporeactivity when compared to those in Sham group. When SR141716A or AM251 was administered, the MAP response to NE was （41.75±4.08） mmHg or （44.78±1.80） mmHg respectively, which was higher than that in saline groups with （4.31±0.36） mmHg （P 〈0.01）. We also showed an increased 4-hour survival rate in the SR141716A or AM251-treated group with 20% or 30%, but with a statistically significant difference present between the AM251-treated and saline groups （P 〈0.05）. Conclusions CBIR is involved in vascular hyporeactivity resulting from hemorrhagic shock in rats, and CB1R antagonist may be useful in treating patients with traumatic, hemorrhagic shock who need field-rescue or initial treatment.
基金This work was supported by the grants from Jiangsu Province Key Medical Center （No. ZX200608）, the National Nature Science Foundation of China （No. 30672140, No. 81071451）, the Colleges and Universities Natural Science Foundation in Jiangsu Province （No. 10KJB320019）, the Key Project Surpported by the Medical Science and Technology Department Foundation, Jiangsu Province, Department of Health （No. H201012） and the Social Development Projects in Suzhou （No. SS08020）.
文摘Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.
基金supported by the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior-Brasil(CAPES)(Finance Code 001)
文摘Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan.The nociceptive threshold was measured by von Frey filaments test.Tingenone was administered orally 60 min before carrageenan injection.To evaluate the involvement of CB2 receptor,endocannabinoids,and microglia,AM630(a CB2 receptor antagonist),MAFP(an inhibitor of an enzyme that hydrolyses endocannabinoids),and minocycline(a microglial inhibitor)were given intrathecally 20 min before tingenone administration.In addition,an immunofluorescence assay was used to evaluate CB2 receptor and CD11 B(a microglial marker)expression in the spinal cord dorsal horn.Results:Tingenone significantly reduced carrageenan-induced hyperalgesia,which was reversed by pretreatment with AM630.MAFP and minocycline potentiated and prolonged the tingenoneinduced antinociception.CD11 B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone,which was reduced by AM630,MAFP,and minocycline.Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.
基金supported by the Zhejiang Province Natural Science Foundation of China(LD22H090003)Key-Area Research and Development Program of Guangdong Province(2019B030335001 and 2018B030334001)+3 种基金the National Natural Science Foundation of China(31871070,82090031,32071097,31871056,and 32170991)the Key R&D Program of Zhejiang Province(2020C03009)Fundamental Research Funds for the Central Universities(2021FZZX001-37)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057).
文摘The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases.Here,we investigated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.
基金Supported by the Program for New Century Excellent Talents in University of China(NosNCET-08-0668, 1154-NCET-002)the Outstanding Youth Foundation of Heilongjiang Province, China(NoJC200706)
文摘A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.
基金Supported by the Research Council of Kermanshah University of Medical Sciences,Kermanshah,Iran for financial support(grant no.:990812).
文摘Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique.The CB1R antagonist rimonabant(1 or 3 mg/kg,i.p.)was administered either at one hour prior to the sample phase for acquisition,or immediately after the sample phase for consolidation,or at one hour before the test phase for retrieval of NOR memory.For the reconsolidation task,rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition,consolidation,and retrieval,but it did not affect the reconsolidation of NOR memory.Rimonabant administration did not affect acquisition,consolidation,and reconsolidation;however,it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings,along with our previous report,would seem to suggest that RSD may affect different phases of recognition memory based on its duration.Importantly,it seems that the CB1R may,at least in part,be involved in the adverse effects of chronic RSD on the retrieval,but not in the acquisition,consolidation,and reconsolidation,of NOR memory.
基金supported by the Study Grant (2007) for Medical Students of Second Military Medical University,China
文摘Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.
