Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity
JOURNAL OF PHYSIOLOGY-LONDON
Authors: Christie, Stewart; O'Reilly, Rebecca; Li, Hui; Wittert, Gary A.; Page, Amanda J.
Abstract
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. 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 nm), 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 G alpha(i/o), or G alpha(q). Low doses (1-10 nm) of mAEA reduced GVA responses to 3 g stretch, whereas high doses (30-100 nm) increased the response. The inhibitory and excitatory effects of mAEA (1-100 nm) were reduced/lost in the presence of a CB1 and TRPV1 antagonist. PKA, G alpha(i/o) or GHSR antagonists prevented the inhibitory effect of mAEA on GVA mechanosensitivity. Conversely, in the presence of a PKC or G alpha(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.
RECONCILED ESTIMATES AND NOWCASTS OF REGIONAL OUTPUT IN THE UK
NATIONAL INSTITUTE ECONOMIC REVIEW
Authors: Koop, Gary; McIntyre, Stuart; Mitchell, James; Poon, Aubrey
Abstract
There is renewed interest in levelling up the regions of the UK. The combination of social and political discontent, and the sluggishness of key UK macroeconomic indicators like productivity growth, has led to increased interest in understanding the regional economies of the UK. In turn, this has led to more investment in economic statistics. Specifically, the Office for National Statistics (ONS) recently started to produce quarterly regional GDP data for the nine English regions and Wales that date back to 2012Q1. This complements existing real GVA data for the regions available from the ONS on an annual basis back to 1998; with the devolved administrations of Scotland and Northern Ireland producing their own quarterly output measures. In this paper we reconcile these two data sources along with UK quarterly output data that date back to 1970. This enables us to produce both more timely real terms estimates of quarterly economic growth in the regions of the UK and a new reconciled historical time-series of quarterly regional real output data from 1970. We explore a number of features of interest of these new data. This includes producing a new quarterly regional productivity series and commenting on the evolution of regional productivity growth in the UK.