Objectives: Lipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1 ^–/– mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation. Design: We evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1 ^–/– mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119 ^–/– mice. Results: Cyp8b1 ^–/– mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1 ^–/– mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1 ^–/– mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1 ^–/– mice. Conclusion: BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis Sativa L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life. CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations. In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.

There is an urgent and unmet clinical need to develop nonpharmacological interventions for chronic pain management because of the critical side effects of opioids. Low-intensity transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly focused 128-element ultrasound transducer to specifically target small mouse brains using dynamic focus steering. We demonstrate that tFUS stimulation at pain-processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (eg, insula) and multisession focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitivity-related and chronic hyperalgesia–associated neural signals after focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting interexperiment intervals, and investigating effects on age, sex, and genotype in a head-fixed awake model. Importantly, tFUS was found to be safe, causing no adverse effects on motor function or the brain’s neuropathology. In conclusion, the validated proof-of-principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects.

Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined. We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB₁ receptor (CB₁Rs) in the gut of mice rendered DIO by chronic access to a high fat and sucrose diet for 60 days inhibits nutrient-induced release of satiation peptides and promotes overeating. Immunoreactivity for CB₁Rs was present in enteroendocrine cells in the mouse’s upper small-intestinal epithelium that produce and secrete the satiation peptide, cholecystokinin (CCK), and expression of mRNA for CB₁Rs was greater in these cells when compared to non-CCK producing cells. Oral gavage of corn oil increased levels of bioactive CCK (CCK-8) in plasma from mice fed a low fat no-sucrose diet. Pretreatment with the cannabinoid receptor agonist, WIN55,212-2, blocked this response, which was reversed by co-administration with the peripherally-restricted CB₁R neutral antagonist, AM6545. Furthermore, monoacylglycerol metabolic enzyme function was dysregulated in the upper small-intestinal epithelium from DIO mice, which was met with increased levels of a variety of monoacylglycerols including the endocannabinoid, 2-arachidonoyl-sn-glycerol. Corn oil failed to affect levels of CCK in DIO mouse plasma; however, pretreatment with AM6545 restored the ability for corn oil to stimulate increases in levels of CCK, which suggests that elevated endocannabinoid signaling at small intestinal CB₁Rs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCK_A receptor antagonist, devazepide. Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CB₁R-mediated inhibition of gut-brain satiation signaling.