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Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear. Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment. Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP. Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.

Introduction: Seizures may result from the hyperexcitable neuronal activity of the brain. Multiple neurotransmitter receptors, including orexin (OX) and endocannabinoids interfere with forming the synaptic responses linked to the seizures. Therefore, this study investigates the involvement of OX-1 (OX1R) and endocannbinoid-1 (CB1R) receptors in the kainate- induced excitability in the synaptic field responses., Material and Methods: Theta pattern used to stimulate Schaffer collaterals and then metal microelectrodes to record the CA1 field excitatory postsynaptic potentials (fEPSPs). Input/ output stimulation and responses and paired- pulse (PP) stimuli employed to measure the state of synaptic activity in normal and kainate- induced seizure-like hyperexcitable activities and the slope of fEPSPs used as a measure of the change in the synaptic activity. Furthermore, agonists and antagonists of OX and endocannabinoids infused to investigate the involvement of their receptors., Result: The results showed that kainate application increased the fEPSP slope either in input stimuli with different intensities/output synaptic responses (I/O), or test pulse stimulated baseline synaptic responses (BSR) and, hence, increased the excitability of field responses in the CA1 region. However, neither kainate nor theta burst stimulation (TBS) could alter the PP stimuli -induced synaptic responses. TBS increased the fEPSP slope of the kainate-applied I/O and BSR, however, the increase was not high enough in BSR to be classified as long-term potentiation (LTP). The single-antagonist OX1R and CB1R administration prevented TBS- induced potentiation and partially recovered the effect by adding eCB or OX agonists in kainate-injected animals. In contrast, OX or combined eCB-OX antagonist application group demonstrated nearly full recovery of LTP induction., Conclusion: Our study concludes that blockade of OX1 or CB1 prevents the induction of LTP, and OX infusion or both receptor blockade recovers the LTP., Competing Interests: Declaration of Competing Interest Authors have no conflict of interests., (Copyright © 2022. Published by Elsevier Ltd.)

Background & Aims: This study aims to investigate the ameliorative effects of resveratrol (RSV) in a high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) rat model, focusing on the gut endocannabinoid system (ECS), regulated by RSV, in the maintenance of gut barrier integrity and inhibition of gut inflammation., Methods and Results: Male Sprague-Dawley (SD) rats were fed HFD with or without RSV for 6 weeks. The HFD caused increase in body weight, liver index, hepatic lipid accumulation, and inflammation, which was inhibited by RSV. RSV also attenuated gut microbial dysbiosis, with an increase in Akkermansia muciniphila, Ruminococcaceae, and Lachnospiraceae, and a decrease in Desulfovibrio. Moreover, RSV led to a reduction of metabolic endotoxemia and colon inflammation in HFD-fed rats. This was indicated by a decrease in bacterial invasion and translocation along with up-regulation of the mRNA levels of occludin, ZO1, claudin1, and down-regulation of FAK, MyD88, and IRAK4 in the distal colon. Furthermore, RSV inhibited HFD-induced elevation in the expression of cannabinoid receptor type 1 (CB1) mRNA and suppressed CB2 mRNA levels in the colon. The RSV-induced benefits regarding enhanced gut barrier integrity and reduced intestinal permeability were abrogated with a CB1 agonist, ACEA, whereas the inhibitory effect of RSV on the intestinal inflammation was abolished by a CB2 antagonist, AM630. Moreover, microbiota depletion using a cocktail of antibiotics was sufficient to block RSV-induced reduction in intestinal permeability and gut inflammation, as well as the altered mRNA expressions of CB1 and CB2 in the distal colon., Conclusions: These data indicate that the ECS, particularly the expressions of CB1 and CB2, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)