Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype

Abstract

The intestinal hormone cholecystokinin (CCK) inhibits food intake via stimulation of vagal afferent neurons (VAN). Recent studies suggest that CCK also regulates the expression of some G protein-coupled receptors and neuropeptide transmitters in these neurons. The aim of the present study was to characterize the expression of cannabinoid (CB)1 receptors in VAN and to determine whether stimulation of these receptors plays a role in regulating neurochemical phenotype. Expression of CB1 in rat VAN was detectable by in situ hybridization or immunohistochemistry after 6 h of fasting and increased to a maximum after 24 h when approximately 50% of neurons in the mid and caudal regions expressed the receptor. Melanin-concentrating hormone (MCH)1 receptors also increased with fasting, but the changes were delayed compared with CB1; in contrast Y2 receptors (Y2R) exhibited reciprocal changes in expression to CB1. Administration of CCK8s (10 nmol ip) to fasted rats decreased expression of CB1 with a t(1/2) of approximately 1 h compared with 3 h for MCH1. The action of CCK8s was inhibited by ghrelin and orexin-A. The CB1 agonist anandamide (intraperitoneally) reversed the effect of CCK8s on CB1, MCH1, and Y2 receptor expression. In contrast, in rats fasted for 18 h, administration of a CB1 antagonist/inverse agonist (AM281 ip) downregulated CB1 expression and increased Y2 receptor expression. Activation of vagal CB1 receptors therefore influences the neurochemical phenotype of these neurons, indicating a new and hitherto unrecognized role for endocannabinoids in gut-brain signaling.

Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity

“…Peripheral CB1 stimulation also enhances fat uptake in adipose tissue, increases de novo lipogenesis in the liver, and decreases energy expenditure in muscle (25)(26)(27)(28). Notably, EC activity in the gut also appears to affect eating behaviors, as peripheral administration of CB1 agonists induce acute hyperphagia, an effect potentially mediated by CB1 receptors on vagal afferents that innervate the gastrointestinal tract ( 29,30 ).…”

The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease

“…However, it is currently unclear how gut endocannabinoids communicate with the brain to regulate food intake. A possibility is that they may act through CB 1 Rs on vagal terminals [24], on sympathetic nerve terminals [25], or indirectly through the modulation of gastrointestinal hormones. In particular, activation of CB 1 Rs in gastric cells induces secretion of ghrelin [26,27], an orexigenic hormone able to increase fat-taste perception [28] and the rewarding value of high-fat diets [29].…”

“…As mentioned earlier, CB 1 Rs are expressed on peripheral terminals of sensory neurons [24] as well as in peripheral parasympathetic [48] and sympathetic terminals [25]. While CB 1 Rs on both vagal afferents and efferents regulate gastrointestinal motility [49], on sensory nerve terminals they may specifically affect food intake because the acute appetite-suppressant effect of rimonabant is abolished by capsaicin-induced sensory deafferentiation [21,50].…”

Complementary and Alternative Medicine for Gastroparesis

“…Effects of cannabinoids on gut motility and visceral sensation are mediated through these receptors, which are expressed on enteric neurons as well as macrophages. [61][62][63][64] The highest density of CB1 and CB2 receptors are found in the myenteric and submucosal plexuses. Additionally, activation of TRPV1 receptors in the hippocampus and the periaqueductal gray matter may contribute to the anticonvulsant 65 and anxiolytic effects of cannabinoids, 66 respectively.…”