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Abstract
The medial subnucleus of the tractus solitarius (mNTS) is a central component of the vago-vagal circuitry that receives sensory input from the viscera and projects to the dorsal motor nucleus of the vagus (DMV), the source of motor output to the stomach. The central hypothesis of my dissertation was that GABA signaling in the mNTS regulates the activity of the vago-vagal circuitry and determines resting gastric tone. Using an in vivo preparation, I microinjected drugs into the mNTS of anesthetized rats while monitoring intragastric pressure (IGP). Microinjection of GABAA receptor antagonists decreased IGP and inhibited motility and was prevented by vagotomy, blockade of ionotropic glutamate receptors or blockade of peripheral muscarinic cholinergic receptors. Using an in vitro brainslice preparation, I performed whole-cell voltage- and current-clamp recordings and found that gastric-projecting mNTS neurons possess tonic as well as phasic GABA currents that regulate excitability of the mNTS. This led to the hypothesis that activation of mu-opioid receptors in the mNTS impacts gastric motility through modulation of local GABA activity. Using an in vivo preparation, I found that stimulation of mu-opioid receptors in the mNTS decreased IGP and was prevented by vagotomy, blockade of mu-opioid receptors, GABAA receptors, ionotropic glutamate receptors, or peripheral muscarinic cholinergic receptors. A subsequent hypothesis was that release of endogenous opioids in the mNTS is a component of the receptive relaxation reflex (RRR). The experimental model of the RRR involves distension of a small balloon in the esophagus that produces a decrease in fundus tone. Using this model for the RRR, I found that the decrease in fundus tone was prevented by prior blockade of mu-opioid receptors in the mNTS or systemic blockade of mu-opioid receptors.
Studies from my dissertation present evidence that (1) there is a high level of intrinsic GABA signaling in the mNTS that regulates gastric motility; (2) there is both tonic and phasic GABA signaling in mNTS neurons; (3) stimulation of mu-opioid receptors in the mNTS inhibits gastric motility by suppressing ongoing GABA activity; and (4) stimulation of a vago-vagal reflex causes release of endogenous opioids in the mNTS that inhibit ongoing GABA activity.
