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Background & Purpose: The constant emergence and broad toxicological effects of synthetic cannabinoids create a discernible public health threat. The synthetic cannabinoid AMB-FUBINACA (AMB-FUB) is a potent agonist at the CB 1 receptor and has been associated with numerous fatalities. Synthetic cannabinoids are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant co-exposures in vivo., Experimental Approach: Male and female C57Bl/6 mice received a single dose of AMB-FUB (3 or 6 mg kg -1 ), pFPP (10 or 20 mg kg -1 ) or vehicle intraperitoneally. Mice were co-exposed to AMB-FUB (3 mg kg -1 ) and pFPP (10 mg kg -1 ) or risperidone (0.5 mg kg -1 ) to investigate these drug combinations. To study receptor-dependency and potential rescue of AMB-FUB toxicity, rimonabant (3 mg kg -1 ) was administered both pre- and post-AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded., Key Results: AMB-FUB induced CB 1 -dependent hypothermia and convulsions in mice. The combination of AMB-FUB and pFPP significantly potentiated hypothermia, as did risperidone pre-treatment. Interestingly, risperidone provided significant protection from AMB-FUB-induced convulsions in female mice. Pre- and post-treatment with rimonabant was able to significantly attenuate both hypothermia and convulsions in mice administered AMB-FUB., Conclusion & Implications: Factors such as dose, CB 1 signalling, and substance co-exposure significantly contribute to the toxicity of AMB-FUBINACA. Mechanistic understanding of synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies and identify vulnerable populations of synthetic cannabinoid users., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatic ischemia/reperfusion (HIR), which can result in severe liver injury and dysfunction, is usually associated with autophagy and endocannabinoid system derangements. Whether or not the modulation of the autophagic response following HIR injury is involved in the hepatoprotective effect of the cannabinoid receptor 1(CB1R) antagonist rimonabant remains elusive and is the aim of the current study. Rats pre-treated with rimonabant (3 mg/kg) or vehicle underwent 30 min hepatic ischemia followed by 6 hrs. reperfusion. Liver injury was evaluated by serum ALT, AST, bilirubin (total and direct levels) and histopathological examination. The inflammatory, profibrotic and oxidative responses were investigated by assessing hepatic tumor necrosis factor α (TNFα), nuclear factor kappa B (NF-κB), transforming growth factor (TGF-β), lipid peroxidation and reduced glutathione. The hepatic levels of CB1R and autophagic markers p62, Beclin-1, and LC3 as well as the autophagic signaling inhibitors ERK1/2, PI3K, Akt and mTOR were also determined. Rimonabant significantly attenuated HIR-induced increases in hepatic injury, inflammation, profibrotic responses and oxidative stress and improved the associated pathological features. Rimonabant modulated the expression of p62, Beclin-1, and LC3, down-regulated CB1R, and dcreased pERK1/2, PI3K, Akt, and mTOR activities. The current study suggests that rimonabant can protect the liver from IR injury at least in part by inducing autophagy, probably by modulating ERK- and/or PI3K/AKT-mTOR signaling., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB 1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB 1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 μM) or SR141716 (0.003-10 μM), cumulative concentrations of WIN 55,212-2 (0.001-30 μM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC 50 values were applied to global regression analysis to determine the pK B . The antagonist potency of cannabidiol at the CB 1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pK B values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pK B values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol's low micromolar CB 1 antagonist pK B values suggest that at clinical blood levels (1-3 μM) it may act as a CB 1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Stimulation of cannabinoid CB 1 receptors generally increases ingestion. However, the non-selective cannabinoid receptor agonist HU-210 exerts the opposite effect. The first objective of this study was to investigate the role of CB 1 receptors in this "atypical" effect. Studies on the endocannabinoid system investigating the microstructure of licking for palatable solutions reported inconsistent results as for the role of CB 1 receptors in "liking" and "wanting". The second objective was to deal with these inconsistencies investigating the within-session time-course of licking-burst number. The microstructure of licking for a 10% sucrose solution in 30-min sessions was analysed in two experiments. In Experiment 1, the effect of the CB 1 receptor antagonist-inverse agonist rimonabant (0.5, 1 mg/kg) on HU-210 effect (100 μg/kg) was investigated. A dose range of HU-210 (25, 50, 100 μg/kg) was examined in Experiment 2. In Experiment 1, both HU-210 and rimonabant reduced licking due to reduced burst number. Moreover, HU-210 reduced the intra-burst lick rate, an index of motor competence. HU-210 effects were antagonised by rimonabant, and vice versa. Rimonabant decreased burst number late in the session at 0.5 mg/kg, and since the beginning of the session at 1 mg/kg. In Experiment 2, HU-210 failed to affect overall ingestion. These results suggest that HU-210 effect - when present - depends on CB 1 receptor stimulation, possibly leading to impairment of the motor competence necessary for licking. The reduction of burst number late in the session observed with rimonabant 0.5 mg/kg, which resembles the effect of reward devaluation, might suggest reduced "liking"., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Circulating levels of bacterial lipopolysaccharide (LPS) or endotoxin are chronically elevated in obesity (metabolic endotoxemia), resulting in low-grade inflammation. Metabolic endotoxemia has been identified as a triggering factor for obesity-associated metabolic complications such as insulin resistance. Furthermore, LPS has been shown to modulate endocannabinoid synthesis and notably to induce cannabinoid receptor type-1 (CB1) ligand synthesis. CB1 activation promotes inflammation, increases food intake and impairs insulin signaling. Therefore, we hypothesized that LPS acts through a CB1-dependent mechanism to aggravate inflammation and promote insulin resistance. Male Wistar rats fed a chow diet were implanted with mini-osmotic pumps delivering a low dose of LPS (n = 20; 12.5 μg/kg body weight (BW)/hr.) or saline (n = 10) continuously for six weeks. LPS-treated rats were injected daily with a CB1 antagonist (Rimonabant, SR141716A; 3 mg/kg, intraperitoneal (ip); LPS + CB1x; n = 10) or vehicle (1 mL/kg, LPS; n = 10). Control and LPS rats' food intake was matched to the LPS + CB1x group level. Despite no significant differences in body weight among groups, chronic exposure to low-level LPS altered hepatic endocannabinoid signaling, increased inflammation, and impaired insulin sensitivity and insulin clearance (P < 0.05). CB1 inhibition significantly attenuated LPS signaling (P < 0.05), which attenuated LPS-induced metabolic alterations. Therefore, we concluded that CB1 contributes to LPS-mediated inflammation and insulin resistance, suggesting that blocking CB1 signaling may have therapeutic benefits in reducing inflammation-induced metabolic abnormalities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Endocannabinoids acting through cannabinoid receptor type 1 (CB1) are major modulators of peripheral somatic and visceral nociception. Although only partially studied, some evidence suggests a particular role of CB1 within the brain in nociceptive processes. As the endocannabinoid system regulates affect and emotional behaviors, we hypothesized that cerebral CB1 influences affective processing of visceral pain-related behaviors in laboratory animals. To study nocifensive responses modulated by supraspinal CB1, we used conditional knock-out mice lacking CB1 either in cortical glutamatergic neurons (Glu-CB1-KO), or in forebrain GABAergic neurons (GABA-CB1-KO), or in principal neurons of the forebrain (CaMK-CB1-KO). These mutant mice and mice treated with the CB1 antagonist SR141716 were tested for different pain-related behaviors. In an acetic acid-induced abdominal constriction test, supraspinal CB1 deletions did not affect nocifensive responses. In the cerulein-model of acute pancreatitis, mechanical allodynia or hyperalgesia were not changed, but Glu-CB1- and CaMK-CB1-KO mice showed significantly increased facial grimacing scores indicating increased affective responses to this noxious visceral stimulus. Similarly, these brain-specific CB1 KO mice also showed significantly changed thermal nociception in a hot-plate test. These results reveal a novel, and important role of CB1 expressed by cortical glutamatergic neurons in the affective component of visceral nociception., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)