Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity

Abstract

Key pointsr The fine control of food intake is important for the maintenance of a healthy metabolic state. r Gastric vagal afferents (GVAs) are involved in the peripheral regulation of food intake via signalling the degree of distension of the stomach which ultimately leads to feelings of fullness and satiety.r This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration-dependent biphasic manner.r This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors.r These data have important implications for the peripheral control of food intake.Abstract Gastric vagal afferents (GVAs) signal to the hindbrain resulting in satiety. Endocannabinoids are endogenous ligands of cannabinoid 1 receptor (CB1) and transient receptor potential vanilloid-1 (TRPV1) channels. The endocannabinoid anandamide (AEA) is expressed in the stomach, and its receptor CB1 is expressed in ghrelin-positive gastric mucosal cells. Further, TRPV1, CB1 and growth hormone secretagogue receptor (ghrelin receptor, GHSR) are expressed in subpopulations of GVA neurons. This study aimed to determine the interaction between TRPV1, CB1, GHSR and endocannabinoids in the modulation of GVA signalling. An in vitro electrophysiology preparation was used to assess GVA mechanosensitivity in male C57BL/6 mice.

Functional interaction between Ghrelin and GLP-1 regulates feeding through the vagal afferent system

“…We also found four groups of stomach-projecting NG neurons on the basis of the expression of GHSR and GLP-1R (both GHSR- and GLP-1R-expressing neurons, 70.8%; GHSR alone, 20.8%; GLP-1 alone, 6.3%; neither, 2.1%). A major portion (91.6%) of stomach-projecting NG neurons expressed GHSR, supporting the previous finding of GHSR expression in 98% of tension-sensitive NG neurons that were retrogradely traced from the stomach 37 . To explore the effect of ghrelin and GLP-1 on the cellular excitability of Glp1r + Ghsr + neurons, we studied these neurons’ intracellular signalling mechanisms.…”

“…Selective deletion of the GLP-1R in NG neurons accelerated gastric emptying in rats 14 . The GHSR is also expressed in tension-sensitive NG neurons that innervate the stomach 37 . Furthermore, ghrelin reduces the mechanosensitivity of gastric vagal afferents in mice and ferrets 38 .…”

Relieving tension: effects of cannabinoids on vagal afferent sensitivity

“…Interestingly, the effect of anadamide in modulating the mechanosensitivity of tension GVAs appears biphasic, reducing sensitivity at low concentrations while enhancing sensitivity at higher concentrations (Christie et al . ). The endocannabinoid system is an important regulator of energy homeostasis, and the well‐recognized effects of cannabis to stimulate appetite and increase food intake are attributed to actions at both central and peripheral cannabinoid 1 receptors (CB1) (Sharkey & Pittman, ).…”

“…Tension‐sensitive GVA neurons were shown to co‐express CB1, transient receptor potential vanilloid 1 (TRPV1) and growth hormone secretagogue (or ghrelin; GHSR) receptors, and interestingly, both the inhibitory and excitatory actions of anandamide on GVA mechanosensitivity were shown to be dependent upon both CB1 and TRPV1 receptor signalling (Christie et al . ). At higher concentrations, anandamide activates TRPV1 receptors both directly (via intracellular actions) and indirectly, via stimulation of CB1 receptors and activation of a Gαq–phospholipase C–protein kinase C signalling pathway.…”

“…The paper by Christie et al . () in the current issue of The Journal of Physiology demonstrates that the endocannabinoid anandamide is the latest in a series of endogenous neuroactive substances that can modulate the sensitivity of tension‐sensitive GVAs.…”