Anatomy and function of group III metabotropic glutamate receptors in gastric vagal pathways

Abstract

Metabotropic glutamate receptors (mGluR) are classified into groups I (excitatory), II and III (inhibitory) mGluR. Activation of peripheral group III mGluR (mGluR4, mGluR6, mGluR7, mGluR8), particularly mGluR8, inhibits vagal afferent mechanosensitivity in vitro which translates into reduced triggering of transient lower oesophageal sphincter relaxations and gastroesophageal reflux in vivo. However, the expression and function of group III mGluR in central gastrointestinal vagal reflex pathways is not known. Here we assessed the expression of group III mGluR in identified gastric vagal afferents in the nodose ganglion (NG) and in the dorsal medulla. We also determined the central action of the mGluR8a agonist S-3,4-DCPG (DCPG) on nucleus tractus solitarius (NTS) neurons with gastric mechanosensory input in vivo. Labelling for mGluR4 and mGluR8 was abundant in gastric vagal afferents in the NG, at their termination site in the NTS (subnucleus gelatinosus) and in gastric vagal motorneurons, while labelling for mGluR6 and mGluR7 was weaker in these regions. DCPG (0.1 nmol or 0.001-10 nmol i.c.v.) inhibited or markedly attenuated responses of 8/10 NTS neurons excited by isobaric gastric distension with no effect on blood pressure or respiration; 2 NTS neurons were unaffected. The effects of DCPG were significantly reversed by the group III mGluR antagonist MAP4 (10 nmol, i.c.v.). In contrast, 4/4 NTS neurons inhibited by gastric distension were unaffected by DCPG. We conclude that group III mGluR are expressed in peripheral and central vagal pathways, and that mGluR8 within the NTS selectively reduce excitatory transmission along gastric vagal pathways.