Role Of Cannabinoid Receptors Research Articles

The role of Cannabinoid receptors in visceral pain sensation of rat: an interventional study

Visceral pain, originating from internal organs, represents a challenging aspect of pain management due to its intricate mechanisms and often debilitating nature. Understanding the underlying pathways involved in visceral pain perception is crucial for developing effective therapeutic strategies. The current study aimed to delve into recent advancements in the understanding of cannabinergic modulation of visceral pain perception, focusing on findings from interventional studies utilizing animal models, particularly rats. A total of 30 male rats aged 3 months, with an average weight of 220 g were randomly divided into 3 groups. The groups contained the control group which received intraperitoneal injection of normal saline, the second group received an intraperitoneal injection of anandamide (2 mg/kg), and the third group received an intraperitoneal injection of tramadol (20 mg/kg). The pain in all groups assessed by acetic acid test. The data obtained from the intraperitoneal injection of anandamide to the rats of the experimental group showed a significant decrease in the amount of perceived visceral pain compared to control group. In addition, the results showed that tramadol injection significantly decreased visceral pain in experimental group 2 compared to the control group. In conclusion, the current study provides an evidence for the involvement of cannabinoid receptors in the modulation of visceral pain sensation in rats.

The role of cannabinoid receptor 2 in bone remodeling during orthodontic tooth movement

BackgroundThe purpose of this study is to explore the effects of CB2 on bone regulation during orthodontic tooth movement.MethodsThirty male mice were allocated into 2 groups (n = 15 in each group): wild type (WT) group and CB2 knockout (CB2−/−) group. Orthodontic tooth movement (OTM) was induced by applying a nickel-titanium coil spring between the maxillary first molar and the central incisors. There are three subgroups within the WT groups (0, 7 and 14 days) and the CB2−/− groups (0, 7 and 14 days). 0-day groups without force application. Tooth displacement, alveolar bone mass and alveolar bone volume were assessed by micro-CT on 0, 7 and 14 days, and the number of osteoclasts was quantified by tartrate-resistant acid phosphatase (TRAP) staining. Moreover, the expression levels of RANKL and OPG in the compression area were measured histomorphometrically.ResultsThe WT group exhibited the typical pattern of OTM, characterized by narrowed periodontal space and bone resorption on the compression area. In contrast, the accelerated tooth displacement, increased osteoclast number (P < 0.0001) and bone resorption on the compression area in CB2−/− group. Additionally, the expression of RANKL was significantly upregulated, while OPG showed low levels in the compression area of the CB2 − / − group (P < 0.0001).ConclusionsCB2 modulated OTM and bone remodeling through regulating osteoclast activity and RANKL/OPG balance.

Production of anti-human cannabinoid receptor 2 (CB2) monoclonal antibody using non-viral vector induced human CB2 expressing myeloma as an immunogen.

Cannabinoid receptor 2 (CB2) of the cannabinoid system is predominantly expressed on immune cells and involved in a diverse range of immune functions. However, the role of CB2 in immunoregulation is still controversial. One of the challenges in the detailed characterization and functional study of CB2 is the lack of CB2-specific monoclonal antibodies (mAbs). We aimed to produce mAbs against a native form of human CB2 using human CB2 expressing mouse myeloma cells as immunogens. Non-viral vector expression system was used to generate stable human CB2-expressing mouse myeloma cells and were utilized as an immunogen for mouse immunization. Hybridoma technique was employed in the production of mAbs. The produced mAbs were verified by flow cytometry and western blotting. Using a non-viral vector expression system, myeloma clones, which stable expressed human CB2, were generated and used as immunogen for antibody production. Following mouse immunization process, the anti-CB2 polyclonal antibodies were induced. By hybridoma technique, a mAb against CB2 could be generated. This mAb reacted to CB2-expressing THP-1 cells, but not to non-CB2-expressing SH-SY5Y cells. By western blotting, the generated anti-CB2 mAb reacted with a 42 kDa protein presented in lysates of CB2-expressing THP-1 cells, but not with non-CB2-expressing SH-SY5Y cell lysates. A new approach using human CB2 expressing myeloma cells as immunogen for production of anti-CB2 mAb was developed. The generated anti-human CB2 mAb is regarded as a valuable tool for CB2 characterization. Moreover, the developed technique can be applied to produce other antibodies of interest.

Cannabinoid receptor 2 alleviates sepsis-associated acute lung injury by modulating maturation of dendritic cells

BackgroundDendritic cells (DCs) play a key role in a variety of inflammatory lung diseases, but their role in sepsis-associated acute lung injury (SA-ALI) is currently not been illuminated. Cannabinoid receptor 2 (CNR2) has been reported to regulate the DCs maturation. However, whether the CNR2 in DCs contributes to therapeutic therapy for SA-ALI remain unclear. In current study, the role of CNR2 on DCs maturation and inflammatory during SA-ALI is to explored. MethodsFirst, the CNR2 level was analyzed in isolated Peripheral Blood Mononuclear Cells (PBMCs) and Bronchoalveolar Lavage Fluid (BALF) from patient with SA-ALI by qRT-PCR and flow cytometry. Subsequently, HU308, a specific agonist of CNR2, and SR144528, a specific antagonist of CNR2, were introduced to explore the function of CNR2 on DCs maturation and inflammatory during SA-ALI. Finally, CNR2 conditional knockout mice were generated to further confirm the function of DCs maturation and Inflammation during SA-ALI. ResultsFirst, we found that the expression of CNR2 on DCs was decreased in patient with SA-ALI. Besides, the result showed HU308 could decrease the maturation of DCs and the level of inflammatory cytokines, simultaneously reduce pulmonary pathological injury after LPS-induced sepsis in mice. In contrast of HU308, SR144528 exhibits opposite function of DCs maturate, inflammatory cytokines and lung pathological injury. Furthermore, comparing with SR144528 treatment, similar results were obtained in DCs specific CNR2 knockout mice after LPS treatment. ConclusionCNR2 could alleviate SA-ALI by modulating maturation of DCs and inflammatory factors levels. Targeting CNR2 signaling specifically in DCs has therapeutic potential for the treatment of SA-ALI.

Library Screening and Preliminary Characterization of Synthetic Cannabinoids Against Prostate and Pancreatic Cancer Cell Lines.

Background: Our previous screening efforts with colorectal cancer cell lines suggested potential cannabinoid therapeutic leads for other solid cancers. Objectives: The aim of this study was to identify cannabinoid lead compounds that have cytostatic and cytocidal activities against prostate and pancreatic cancer cell lines and profile cellular responses and molecular pathways of select leads. Materials and Methods: A library of 369 synthetic cannabinoids was screened against 4 prostate and 2 pancreatic cancer cell lines with 48 h of exposure at 10 μM in medium with 10% fetal bovine serum using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay. Concentration titration of the top 6 hits was carried out to identify their concentration-response patterns and calculate IC50 values. Three select leads were examined for cell cycle, apoptosis, and autophagy responses. The role of cannabinoid receptors (CB1 and CB2) and noncanonical receptors in apoptosis signaling was examined with selective antagonists. Results: Two independent screening experiments in each cell line detected growth inhibitory activities against all six or a majority of cancer cell lines for HU-331 (a known cannabinoid topoisomerase II inhibitor), (±)5-epi-CP55,940, and PTI-2, each previously identified in our colorectal cancer study. 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 were novel hits. Morphologically and biochemically, (±)5-epi-CP55,940 elicited caspase-mediated apoptosis of PC-3-luc2 (a PC-3 subline with luciferase) prostate cancer and Panc-1 pancreatic cancer cell lines, each the most aggressive of the respective organ site. The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB2 antagonist, SR144528, but not modulated by the CB1 antagonist, rimonabant, and GPR55 antagonist, ML-193, nor TRPV1 antagonist, SB-705498. In contrast, 5-fluoro NPB-22 and FUB-NPB-22 did not cause substantial apoptosis in either cell line, but resulted in cytosolic vacuoles and increased LC3-II formation (suggestive of autophagy) and S and G2/M cell cycle arrests. Combining each fluoro compound with an autophagy inhibitor, hydroxychloroquine, enhanced the apoptosis. Conclusions: 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 represent new leads against prostate and pancreatic cancer cells in addition to the previously reported compounds, HU-331, (±)5-epi-CP55,940, and PTI-2. Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D.

The Endocannabinoid System as a Biomarker for Diagnostic and Therapeutic Applications in Depression and Anxiety.

Depression and anxiety belong to a family of mental disturbances that have increased significantly in recent years. The etiology of both disorders comprises multiple and complex factors, from genetic background to environmental influence. Since depression and anxiety present severe symptoms, they represent a greater clinical burden and greater therapeutic difficulty. Currently, standardized diagnostic procedures for depression and anxiety allow for the addition of further treatments, including psychotherapy and/or pharmacological intervention, with effective outcomes. However, further steps should be considered with regard to consideration of the endocannabinoid system's role in depression and anxiety. This study aimed to review the evidence from animal research and clinical studies on the role of cannabinoid receptors, the major endocannabinoids -anandamide (AEA) and 2-arachidonoylglycerol (2-AG)- and the enzymes related to the synthesis and degradation of these chemicals as putative biomarkers for diagnostic and therapeutic elements of depression and anxiety. This review included the online search, identification, and analysis of articles (basic and clinical trials) published in English in PubMed linked to the role of cannabinoid receptors, AEA, 2- AG, and the enzymes associated with the synthesis and degradation of these endocannabinoids in depression and anxiety. The neurobiological relevance of the endocannabinoid system offers genetic or pharmacological manipulation of this system as a potential strategy for the diagnostic and clinical management of mood disorders, including depression and anxiety. Although the described approach in this review is promising, no solid evidence is yet available, and along with additional experiments using animal models that mimic human depression and anxiety, clinical trials are needed to explore the role of the endocannabinoid system's elements as well as the anandamide membrane transporter, none of which have been adequately studied in depression and anxiety.

Role of cannabinoid receptor-2 in small intestinal fasted myoelectric activity of rats

Cannabinoid receptor-1 (CB1R) and cannabinoid receptor-2 (CB2R) have significant roles in the esophagus, small intestine, and colon motility in the postprandial period besides gastric emptying, secretion, and defecation in the gastrointestinal system. Furthermore, our previous study showed that activation of peripheral CB1R inhibited migrating myoelectric complex (MMC), forming the source of fasted small intestinal motility. However, the role of the central/peripheral CB2Rs on the MMC pattern is still unknown. The present study aimed to investigate the roles of peripheral and central CB2Rs in forming and regulating small intestine MMC patterns in rats. In this study, we used 42 adult male Sprague-Dawley rats (n:7). We implanted bipolar electrodes in three different jejunum sites of rats (J1, J2, J3) to record the MMC pattern. We placed a cannula in the right lateral ventricle to perform drug intracerebroventricularly (i.c.v.) and implanted a catheter in the right jugular vein to inject the drug intravenously (i.v). After the amelioration period, we conducted experiments following an 18-hour fasting period and later took at least a one-hour baseline recording of the MMC pattern. Then, we injected JWH 133, a CB2R agonist i.v. (1.25-10 mg/kg) or i.c.v. (2.5- 20 μg/rat) and also administered AM 630, a CB2R antagonist, i.v. (0.25-2 mg/kg) or i.c.v. (2.5-20 μg/rat). We compared the effects of JWH 133 or AM 630 on the MMC pattern to the vehicle group (10% dimethyl sulfoxide). Centrally or peripherally injected JWH 133 and AM 630 did not cause any change in the spike frequency and the number of the MMC cycle. The results of the present study propose that CB2Rs are involved in neither endogenous formation nor exogenous regulation of the fasting myoelectric activity in healthy fasted rats.

Anti-Inflammatory and Pro-Autophagy Effects of the Cannabinoid Receptor CB2R: Possibility of Modulation in Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from loss of insulin-secreting β-cells in islets of Langerhans. The loss of β-cells is initiated when self-tolerance to β-cell-derived contents breaks down, which leads to T cell-mediated β-cell damage and, ultimately, β-cell apoptosis. Many investigations have demonstrated the positive effects of antagonizing cannabinoid receptor 1 (CB1R) in metabolic diseases such as fatty liver disease, obesity, and diabetes mellitus, but the role of cannabinoid receptor 2 (CB2R) in such diseases is relatively unknown. Activation of CB2R is known for its immunosuppressive roles in multiple sclerosis, rheumatoid arthritis, Crohn’s, celiac, and lupus diseases, and since autoimmune diseases can share common environmental and genetic factors, we propose CB2R specific agonists may also serve as disease modifiers in diabetes mellitus. The CNR2 gene, which encodes CB2R protein, is the result of a gene duplication of CNR1, which encodes CB1R protein. This ortholog evolved rapidly after transitioning from invertebrates to vertebrate hundreds of million years ago. Human specific CNR2 isoforms are induced by inflammation in pancreatic islets, and a CNR2 nonsynonymous SNP (Q63R) is associated with autoimmune diseases. We collected evidence from the literature and from our own studies demonstrating that CB2R is involved in regulating the inflammasome and especially release of the cytokine interleukin 1B (IL-1β). Furthermore, CB2R activation controls intracellular autophagy and may regulate secretion of extracellular vesicles from adipocytes that participate in recycling of lipid droplets, dysregulation of which induces chronic inflammation and obesity. CB2R activation may play a similar role in islets of Langerhans. Here, we will discuss future strategies to unravel what roles, if any, CB2R modifiers potentially play in T1DM.

The role of cannabinoid receptor 2 in microglial clearance of human tau.

It is well accepted that neuroinflammation is a key component in the pathobiology of Alzheimer's disease (AD). Multiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in AD patients. The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed-competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. Moreover, the pharmacological modulation of CB2 using CB2-selective compounds have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD-related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation. Brain slice cultures will be generated from CB2-EGFP knock-in mice and transduced with virus-mediated tau previously shown to accumulate total tau and develop insoluble tau species. Brain slices will be evaluated for tau pathology and microglial phenotypes using real-time imaging and biochemical analyses. Previous investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 to alter the function of immune cells and reduce accumulation of toxic human alpha-synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. We are currently working with brain slice cultures to evaluate how CB2 alters the behavior of microglia including phagocytosis and clearance of human tau. These studies will advance our understanding of the role of CB2 in the microglial contribution to pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.

A role for cannabinoid receptors in ethanol-dependent pulmonary immune activation

A role for cannabinoid receptors in ethanol-dependent pulmonary immune activation

The Inhibition of the Degrading Enzyme Fatty Acid Amide Hydrolase Alters the Activity of the Cone System in the Vervet Monkey Retina.

Recent studies using full-field electroretinography (ffERG) that triggers a non-specific mass response generated by several retinal sources have attributed an important role for cannabinoid receptors in mediating vision in primates. Specific cone-mediated responses evoked through the photopic flicker ERG appear to be a better way to validate the assumption that endogenous cannabinoids modulate the cone pathway, since FAAH is mainly expressed in the vervet monkey cone photoreceptors. The aim of this study is two-fold: (1) to use the photopic flicker ERG to target the cone pathway specifically, and (2) use URB597 as a selective inhibitor of the endocannabinoid degrading enzyme Fatty Acid Amide Hydrolase (FAAH) to enhance the levels of fatty acid amides, particularly anandamide. We recorded ERGs under four different flicker frequencies (15, 20, 25, and 30 Hz) in light-adapted conditions after intravitreal injections of URB597. Our results show that intravitreal injections of URB597, compared to the vehicle DMSO, increased significantly ffERG amplitudes at 30 Hz, a frequency that solely recruits cone activity. However, at 15 Hz, a frequency that activates both rods and cones, no significant difference was found in the ERG response amplitude. Additionally, we found no differences in implicit times after URB597 injections compared to DMSO vehicle. These results support the role of molecules degraded by FAAH in cone-mediated vision in non-human primates.

Cannabinoid receptors promote chronic intermittent hypoxia-induced breast cancer metastasis via IGF-1R/AKT/GSK-3β

The progression of breast cancer is closely related to obstructive sleep apnea-hypopnea syndrome (OSAHS). Low concentrations of cannabinoids promote tumor proliferation. However, the role of cannabinoid receptors (CBs) in chronic intermittent hypoxia (CIH)-induced breast cancer has not been reported. The migration and invasion of breast cancer cell lines (MCF-7 and T47D) were measured by scratch assay and transwell assay. Gene and protein expressions were analyzed by qPCR and western blotting. Tumor xenograft mice model were established to evaluate the function of CBs. We observed that chronic hypoxia (CH) and CIH increased CBs expression and promoted migration and invasion in breast cancer. Mice grafted with MCF-7 exhibited obvious tumor growth, angiogenesis, and lung metastasis in CIH compared with CH and control. In addition, CIH induced CBs expression, which subsequently activated insulin-like growth factor-1 receptor (IGF-1R)/AKT/glycogen synthase kinase-3β (GSK-3β) axis. Knockdown of CBs alleviated CIH-induced migration and invasion of breast cancer in vitro. Furthermore, CIH exaggerated the malignancy of breast cancer and silencing of CBs suppressed tumor growth and metastasis in vivo. Our study contributed to understanding the role of CIH in breast cancer development modulation.

Association of Breast Tumour Expression of Cannabinoid Receptors CBR1 and CBR2 with Prognostic Factors and Survival in Breast Cancer Patients.

Cannabinoid receptors (CBR) are potential therapeutic targets for breast cancer. However, the role of CBR in breast cancer survival remains poorly understood. Data from a prospective cohort of 522 women diagnosed with invasive breast cancer between 2010 and 2012 were analysed. Clinical and pathological features were retrieved from electronic medical records. CBR expression was measured by immunohistochemistry. Adjusted partial Spearman correlations and multivariate Cox models were used to estimate associations with breast cancer prognostic factors and survival, respectively. The median follow-up was 92.0 months (range 7.0–114.0). CBR expression was heterogenous in tumours. Cytoplasmic expression of CBR1 was positively correlated with lymph node invasion (rs = 0.110; p = 0.0155) and positive status of the human epidermal growth factor receptor 2 (HER2) (rs = 0.168; p = 0.0002), while nuclear CBR2 was negatively correlated with grade (rs = −0.171; p = 0.0002) and positively correlated with oestrogen receptor and progesterone receptor-positive status (rs = 0.173; p = 0.0002 and rs = 0.121; p = 0.0084, respectively). High cytoplasmic expression of CBR2 was associated, with 13% higher locoregional and distant recurrences (HR = 1.13 [0.97–1.33]), though this association did not reach statistical significance. Although the few events occurring during follow-up may have limited the detection of significant associations, these results indicate that CBR expression in breast cancer deserves further investigation.

Short and long-term neuroprotective effects of cannabidiol after neonatal peripheral nerve axotomy

Neonatal rat sciatic nerve crush mimics obstetric axonotmesis, leading to extensive loss of motor and sensory neurons. The present study aimed to investigate the neuroprotective potential of cannabidiol (CBD) and the role of cannabinoid receptors after sciatic nerve crush in neonatal rats. For that, two-day-old Wistar rats were used, organized into the following experimental groups: sciatic nerve crush plus CBD treatment (CBD), crush plus vehicle treatment (VE), crush + CBD + AM251 treatment (AM251 – CB1 inverse agonist), crush + CBD + AM630 treatment (AM630 – CB2 antagonist). Spinal motoneuron survival was evaluated by Nissl staining of the lumbar spinal cord, 5- and 56-days following injury. CBD treatment enhanced neuronal survival by ~54 % both 5 days and 8 weeks after injury. However, AM251 and AM630 treatment decreased neuronal rescue by 30 % when compared to the CBD group, suggesting that CBD acts partially through such pathways. However, in the long term, only the CB1 blockade reverted CBD positive results. Synaptic preservation was evaluated by anti-synaptophysin immunolabeling. Five days after the lesion, CBD treatment preserved ~35 % of synapses in the ventral horn, and such effect was partially reversed by CB1 inactivation. Additionally, CBD treatment reduced astroglial reaction both at 5 days (39 %, compared to VE) and 8 weeks (31 %, compared to VE) after lesion. The microglial response was acutely reduced by 62 % after CBD treatment. Overall, the results herein show that CBD is neuroprotective, increasing neuronal survival and reducing glial reaction after neonatal axotomy. Such effects require CB1 and CB2 receptors to be effective, in turn influencing neuroprotection, glial reactivity, and functional recovery.

Changes in sleep-wake cycle after microinjection of agonist and antagonist of endocannabinoid receptors at the medial septum of rats

The role of medial septum in the genesis of slow-wave sleep and the inhibition of rapid eye movement sleep has been established using neurotoxic lesion and chemical stimulation of the medial septum. Intracerebroventricular injection of endocannabinoids (anandamide) decreases wake and increases slow-wave and rapid eye movement sleep in rats. Central cannabinoid (CB1) receptors are localized in the rat medial septum; however, the role of cannabinoid receptors at the medial septum on the regulation of sleep-wakefulness in rats lacks evidence. In this study, we have examined the changes in sleep architecture of 21 male Wistar rats, divided into three groups. Initially, 6 rats were used for dose standardization. Subsequently, one group (n = 6) was microinjected with CB1 receptor agonist, R-(+)-WIN 55,212–2 mesylate salt, the second group (n = 6) received microinjection of CB1 receptor antagonist LY 320,135, and the third group (n = 5) was microinjected with the vehicle, DMSO at the medial septum using stereotaxy. The sleep-wake cycle was recorded using electroencephalogram, electro-oculogram, and electromyogram. Microinjection of CB1 receptor agonist at the medial septum decreased slow-wave sleep and increased total sleep time. The increase in total sleep time was due to an increased percentage of rapid eye movement sleep. After the third and fourth hour of CB1 receptor antagonist microinjection at the medial septum, slow-wave sleep decreased when compared to vehicle injection, while rapid eye movement sleep decreased compared to baseline. We conclude that the endocannabinoid system at the septal nucleus acts through CB1 receptors to increase rapid eye movement sleep in rats.

The Role of Cannabinoid Receptors and TRPV1 Channel in the Infarct‐Reducing Effect of Cold Adaptation

An increase in cardiac tolerance to ischemia/reperfusion (I/R) is an urgent aim of physiology, pharmacology, and cardiac surgery, since I/R injury to the heart is often the cause of cardiogenic shock and subsequent death of patients in the postoperative period. We hypothesized that chronic continuous cold exposure can alter cardiac tolerance to I/R. Male Wistar rats were exposed to continuous cold exposure (+4°C, for 4 weeks). Rats which were subjected to coronary artery occlusion (45 min) and reperfusion (2 h) 24 h after cold adaptation. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant, the selective CB2 receptor antagonist AM-630, the transient receptor potential vanilloid channel (TRPV1) inhibitor capsazepine was administered intravenously 15 min before coronary artery occlusion. Chronic cold exposure enhanced tolerance to cold (–18○C for 4 h), increased brown fat weight, adrenal weight, heart weight and serum triiodothyronine level but does not alter thymus, spleen weight, serum cortisol, corticosterone, and thyroxin levels. It was found that cold adaptation promoted a decrease in the infarct size/area at risk ratio by 33%. It was demonstrated that cannabinoid receptor antagonists did not eliminate the infarct-reducing effect of cold adaptation. Capsazepine completely abolished the infarct-limiting effect of cold adaptation. It was concluded that TRPV1 channel is involved in chronic cold-induced cardiac tolerance to I/R.

Research progress on the roles of cannabinoid receptors in cardiovascular diseases

大麻素受体（CBR）是内源性大麻素系统的重要组成部分，介导了内源性大麻素或外源性大麻类似物的胞内信号转导，广泛参与心血管疾病的发生发展过程。CBR主要包括经典的1型及2型大麻素受体，以及新型的瞬时受体电位香草酸亚型1、过氧化物酶体增殖物激活受体和其他G蛋白耦联受体。该文综述了CBR的结构及组织分布特点，以及CBR在高血压、心肌肥厚、心力衰竭、动脉粥样硬化、心肌缺血再灌注损伤及糖尿病心肌病等发生发展中的作用及其机制。.

Transcriptomic Changes and the Roles of Cannabinoid Receptors and PPARγ in Developmental Toxicities Following Exposure to Δ9-Tetrahydrocannabinol and Cannabidiol.

Human consumption of cannabinoid-containing products during early life or pregnancy is rising. However, information about the molecular mechanisms involved in early life stage Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) toxicities is critically lacking. Here, larval zebrafish (Danio rerio) were used to measure THC- and CBD-mediated changes on transcriptome and the roles of cannabinoid receptors (Cnr) 1 and 2 and peroxisome proliferator activator receptor γ (PPARγ) in developmental toxicities. Transcriptomic profiling of 96-h postfertilization (hpf) cnr+/+ embryos exposed (6 - 96 hpf) to 4 μM THC or 0.5 μM CBD showed differential expression of 904 and 1095 genes for THC and CBD, respectively, with 360 in common. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in the THC and CBD datasets included those related to drug, retinol, and steroid metabolism and PPAR signaling. The THC exposure caused increased mortality and deformities (pericardial and yolk sac edemas, reduction in length) in cnr1-/- and cnr2-/- fish compared with cnr+/+ suggesting Cnr receptors are involved in protective pathways. Conversely, the cnr1-/- larvae were more resistant to CBD-induced malformations, mortality, and behavioral alteration implicating Cnr1 in CBD-mediated toxicity. Behavior (decreased distance travelled) was the most sensitive endpoint to THC and CBD exposure. Coexposure to the PPARγ inhibitor GW9662 and CBD in cnr+/+ and cnr2-/- strains caused more adverse outcomes compared with CBD alone, but not in the cnr1-/- fish, suggesting that PPARγ plays a role in CBD metabolism downstream of Cnr1. Collectively, PPARγ, Cnr1, and Cnr2 play important roles in the developmental toxicity of cannabinoids with Cnr1 being the most critical.

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome.

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

Role of Cannabinoid Receptors in Psychological Disorder

Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system. Cannabinoid CB1 and CB2 receptors are G protein-coupled receptors present from the early stages of gestation, which is involved in various physiological processes, including appetite, pain-sensation, mood, and memory. Due to the lipophilic nature of cannabinoids, it was initially thought that these compounds exert several biological effects by disrupting the cell membrane nonspecifically. Recent biochemical and behavioral findings have demonstrated that blockade of CB1 receptors engenders antidepressant-like neurochemical changes (increases in extracellular levels of monoamines in cortical but not subcortical brain regions) and behavioral effects consistent with antidepressant/antistress activity. We aim to define various roles of cannabinoid receptors in modulating signaling pathways and association with several pathophysiological conditions.