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.
Endocannabinoids ; Humans ; Neuralgia ; Receptor, Cannabinoid, CB1 ; Receptor, Cannabinoid, CB2

BACKGROUND: Cannabinoid receptor agonists can reverse opioidinduced nausea and vomiting in animals, but have not yet been tested against opioid-induced pruritus. This study tests the hypothesis that a cannabinoid receptor agonist will prevent opioidinduced pruritus and evaluates if the use of a cannabinoid receptor agonist will increase the analgesic efficacy of opioids. METHODS: Various doses of fentanyl were injected subcutaneously in mice to obtain a dose-response curve with the use of a writhing test. To observe the analgesic potentiation of the cannabinoid agonist WIN55,212-2 in the writhing test, mice were pretreated with various concentrations of WIN55,212-2 (0.25, 0.5, 1.0, 2.0 mg/kg) 10 min prior to the injection of an ED50 dose of fentanyl, as determined from the dose-response curve. To observe the antipruritogenic effect of WIN55,212-2 in a scratching test, mice were pretreated with WIN55,212-2 (0.25, 0.5 mg/kg) 20 min prior to fentanyl injection. A CB1 receptor selective antagonist, AM251 (3 mg/kg), was used to confirm the cannabinoid receptor selectivity. RESULTS: The ED50 of fentanyl in the writhing test was 0.018 mg/kg (range, 0.011?0.025 mg/kg). A dose of 1 mg/kg WIN55,212-2 increased the analgesic efficacy of fentanyl significantly (P < 0.001), but doses of 0.25 mg/kg and 0.5 mg/kg did not increase the analgesic efficacy. A dose of 0.25 mg/kg WIN55,212-5 reduced the scratching response of fentanyl significantly (P < 0.001) and this action was a cannabinoid receptor selective response. CONCLUSIONS: These results demonstrate that 0.25 mg/kg WIN55,212-2 can prevent opioid-induced pruritus. The antipruritogenic activity of WIN55,212-2 occurs at CB1 receptors even if the analgesic efficacy of fentanyl cannot be increased.
Analgesics, Opioid ; Animals ; Cannabinoid Receptor Agonists ; Fentanyl ; Mice ; Nausea ; Piperidines ; Pruritus ; Pyrazoles ; Receptor, Cannabinoid, CB1 ; Receptors, Cannabinoid ; Vomiting

Animals ; Cannabinoid Receptor Modulators ; Liver ; metabolism ; Liver Cirrhosis, Experimental ; metabolism ; parasitology ; Male ; Mice ; Mice, Inbred Strains ; Receptor, Cannabinoid, CB1 ; metabolism ; Schistosoma mansoni ; Schistosomiasis mansoni ; metabolism

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.
Animals ; Appointments and Schedules ; Cannabinoids* ; Controlled Substances ; Jurisprudence ; Korea ; Mass Screening ; Membranes ; Mice ; Receptor, Cannabinoid, CB1 ; Rodentia ; Social Problems

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.
Cannabinoids ; Humans ; Mental Disorders/diagnostic imaging* ; Neurodegenerative Diseases/diagnostic imaging* ; Neurons ; Positron-Emission Tomography ; Receptor, Cannabinoid, CB1

BACKGROUND/AIMS: This study was designed to investigate the possibility that the enhanced nociceptive responsiveness associated with canabonoid type 1 receptors (CB1Rs) and identify its role in mediating visceral hypersensitivity induced by chronic restraint stress. METHODS: Rats were exposed to daily partial restraint stress or sham partial restraint stress with intraperitoneal injection of the vehicle, CB1R agonist or antagonist for 4 consecutive days. We tested the visceromotor reflex to colorectal distention at day 0 and 5. Reverse-transcription polymerase chain reaction and Western blot were used to assess the expression of CB1Rs. RESULTS: Intraperitoneal CB1 agonist (ACEA) injection significantly diminished (p < 0.05) the enhanced visceromotor reflex to colorectal distention at day 5 in stressed rats. Change in electromyogram response after ACEA over baseline, at pressure of 40 mmHg (+13.3 +/- 2.2), 60 mmHg (+15.3 +/- 2.8) and 80 mmHg (+17.0 +/- 4.0) were much lower than in the control animals, which were +35.9 +/- 5.1, +41.1 +/- 6.3 and +54.1 +/- 9.6, respectively. Whereas, CB1 antagonist (SR141716A) had an opposite effect. Compared with control group, the change in electromyogram response after SR141716A over baseline was significantly enhanced (p < 0.05) for the distending pressure of 40 mmHg (+56.0 +/- 10.3), 60 mmHg (+74.6 +/- 12.3) and 80 mmHg (+82.9 +/- 11.0), respectively. Reverse-transcription polymerase chain reaction and Western blotting demonstrated the stress-induced up-regulation of colon CB1Rs (p < 0.05). CONCLUSIONS: Our results suggest there is a key contribution of peripheral CB1Rs involved in the maintenance of visceral hyperalgesia after repeated restraint stress, providing a novel mechanism for development of peripheral visceral sensitization.
Animals ; Blotting, Western ; Colon ; Hyperalgesia ; Hypersensitivity ; Injections, Intraperitoneal ; Irritable Bowel Syndrome ; Negotiating ; Piperidines ; Polymerase Chain Reaction ; Pyrazoles ; Rats ; Receptor, Cannabinoid, CB1 ; Receptors, Cannabinoid ; Reflex ; Salicylamides ; Up-Regulation

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.
Adipocytes* ; Adipogenesis ; Dopamine* ; Endocannabinoids ; Ethanolamine ; Felodipine ; Glycerol ; Humans ; Mesenchymal Stromal Cells* ; PPAR gamma ; Receptor, Cannabinoid, CB1 ; Receptors, Cannabinoid* ; Signal Transduction ; Transcriptional Activation

This study examined endogenous cannabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development of schistosoma japonicum. 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. Immunofluorescence 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.
Arachidonic Acids/*metabolism ; Endocannabinoids/*metabolism ; Liver Cirrhosis/etiology ; Liver Cirrhosis/*metabolism ; Liver Cirrhosis/parasitology ; Polyunsaturated Alkamides/*metabolism ; Random Allocation ; Receptor, Cannabinoid, CB1/*metabolism ; Receptor, Cannabinoid, CB2/*metabolism ; Schistosomiasis japonica/*complications ; Schistosomiasis japonica/metabolism

OBJECTIVETo observe the expression of cannabinoid receptor 1 (CB1R) mRNA and pathological changes in rat hippocampus after deprivation of rapid eye movement (REM) sleep.

METHODSTotally 42 Sprague-Dawley male rats were randomly divided into cage control (CC), tank control (TC) and the sleep deprivation groups (SD). The SD and TC rats were sacrificed at the end of 1 d, 3 d and 5 d sleep deprivation periods, respectively. The modified multiple platform methods were established for the REM sleep deprivation. CB1R mRNA was measured by reverse transcription-polymerase chain reaction (RT-PCR). The hippocampus sections of different stages were observed with electron microscope.

RESULTIn SD 1 d group, the expression of CB1R mRNA was significantly increased compared with the CC, TC, SD 3 d and SD 5 d groups (P <0.05) while in SD 3 d group it was reduced. The expression of CB1R mRNA of SD 5 d group was significantly higher than that of the SD 3 d group (P <0.05). Neuron apoptosis was found in SD 3 d and SD 5 d groups.

CONCLUSIONSleep deprivation can cause brain injury with the changes of CB1R mRNA expression.

Animals ; Hippocampus ; metabolism ; ultrastructure ; Male ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptor, Cannabinoid, CB1 ; biosynthesis ; genetics ; Sleep Deprivation ; metabolism ; pathology ; Sleep, REM

OBJECTIVEIn 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.

METHODSQuantitative autoradiography was used to investigate the binding densities of [(3)H]SR141716A (a selective antagonist) and [(3)H]CP-55940 (an agonist) to the CB1 receptors in the STG. Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre (Australia).

RESULTSContrasting 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 [(3)H]SR141716A and [(3)H]CP-55940 binding.

CONCLUSIONWe suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease.

Adult ; Aged ; Autoradiography ; Case-Control Studies ; Humans ; Middle Aged ; Receptor, Cannabinoid, CB1 ; agonists ; antagonists & inhibitors ; metabolism ; Reference Values ; Schizophrenia ; metabolism ; physiopathology ; Temporal Lobe ; metabolism