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Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity
Author(s) -
Christie Stewart,
O'Rielly Rebecca,
Li Hui,
Wittert Gary A.,
Page Amanda J.
Publication year - 2019
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp278696
Subject(s) - endocannabinoid system , trpv1 , cannabinoid receptor , ghrelin , anandamide , medicine , endocrinology , cannabinoid , growth hormone secretagogue receptor , biology , receptor , chemistry , transient receptor potential channel , agonist , hormone
Key points The fine control of food intake is important for the maintenance of a healthy metabolic state. 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. This study provides evidence that endocannabinoids such as anandamide are capable of regulating GVA sensitivity in a concentration‐dependent biphasic manner. This biphasic effect is dependent upon interactions between the CB1, TRPV1 and GHSR receptors. 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. Effects of methanandamide (mAEA; 1–100 n m ), on GVA responses to stretch were determined in the absence and presence of antagonists of CB1, TRPV1, GHSR, protein kinase‐A (PKA), protein kinase‐C (PKC) and G‐protein subunits Gα i/o , or Gα q . Low doses (1–10 n m ) of mAEA reduced GVA responses to 3 g stretch, whereas high doses (30–100 n m ) increased the response. The inhibitory and excitatory effects of mAEA (1–100 n m ) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, Gα i/o or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or Gα q antagonist the excitatory effect of mAEA was reduced or lost, respectively. Activation of CB1, by mAEA, can activate or inhibit TRPV1 to increase or decrease GVA responses to stretch, depending on the pathway activated. These interactions could play an important role in the fine control of food intake.