μ-Opioid receptor stimulation in the medial subnucleus of the tractus solitarius inhibits gastric tone and motility by reducing local GABA activity

Abstract

We examined the effects of altering mu-opioid receptor (MOR) activity in the medial subnucleus of the tractus solitarius (mNTS) on several gastric end points including intragastric pressure (IGP), fundus tone, and the receptive relaxation reflex (RRR). Microinjection of the MOR agonist [d-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin (DAMGO; 1-10 fmol) into the mNTS produced dose-dependent decreases in IGP. Microinjection of the endogenous MOR agonists endomorphin-1 and endomorphin-2 (20 fmol) into the mNTS mimicked the effects of 10 fmol DAMGO. Microinjection of 1 and 100 pmol DAMGO into the mNTS produced a triphasic response consisting of an initial decrease, a transient increase, and a persistent decrease in IGP. The increase in IGP appeared to be due to diffusion to the dorsal motor nucleus of the vagus. The effects of 10 fmol DAMGO in the mNTS were blocked by vagotomy and by blockade of MORs, GABA(A) receptors, and ionotropic glutamate receptors in the mNTS. The RRR response was abolished by bilateral microinjection of the opioid receptor antagonist naltrexone into the mNTS and reduced by intravenous administration of naltrexone. Our data demonstrate that 1) activation of MORs in the mNTS with femtomole doses of agonist inhibits gastric motility, 2) the mechanism of MOR effects in the mNTS is through suppression of local GABA activity, and 3) blockade of MORs in the mNTS prevents the RRR response. These data suggest that opioids play an important role in mediating a vagovagal reflex through release of an endogenous opioid in the mNTS, which, in turn, inhibits ongoing local GABA activity and allows vagal sensory input to excite second-order mNTS neurons.

Ghrelin increases vagally mediated gastric activity by central sites of action

“…The neurochemical phenotype of these NTS neurons comprises glutamatergic, GABAergic and/or noradrenergic synapses that ultimately terminate onto DMV neurons. Evidence following application of GABAergic antagonists to the DVC, suggests strongly that it is the NTS GABAergic inputs onto DMV neurons which regulate the basal motor outflow to the stomach tonically 35–39 . Studies employing glutamatergic and noradrenergic antagonists within the DVC reveal little effect on basal response in the absence of ancillary reflex or pharmacological manipulation 35,40–42 .…”

Opioidergic consequences of dietary-induced binge eating

“…The mu-opioid receptor selective ligand, DAMGO, inhibits glutamatergic input to the dorsal motor vagus nucleus through pre-synaptic mu-OR containing NTS neurons [64]. Furthermore, reduction in gastric tone are mediated by mu-opioid receptor in the NTS [65]. This suggests that reductions in mu-opioid receptor exhibited by the Binge Access and Continuous Access groups are not only the result of dysregulation of forebrain inputs, but also of gut to hindbrain vago-vagal reflexes.…”

Autonomic Consequences of Spinal Cord Injury

“…Specifically, the dorsal vagal complex (DVC), which consists of the area postrema (AP), the NTS, and the DMV, is an integration center of gastric reflex function at the brainstem level (336). The basal motor outflow to the stomach can be blocked by application of GABA-ergic antagonists to the DVC, suggesting that NTS GABA-ergic projections onto DMV neurons predominantly regulate the tonic activity of the upper GI tract (15,40,131,132,314). Parasympathetic neurons in the DMV are cholinergic and synapse onto postganglionic neurons positioned nearby the stomach via nicotinic receptors.…”