Neurons in the nucleus of the solitary tract (NST) receive information regarding innocuous mechanical and chemical stimulation of the gastrointestinal tract and are part of the central circuitry involved in the parasympathetic regulation of gastrointestinal function. Recent evidence suggests that the NST also receives information regarding high- pressure mechanoreceptor stimulation (a painful stimulus) and is an integral component of the circuits responsible for the response to pain as well as the circuits that modulate pain (antinociceptive pathways). The transmission of two markedly different types of information to the NST raises the fundamental question: How are innocuous and noxious gut stimuli differentiated and processed to ensure the appropriate response to a given stimulus? To address this issue we propose the following hypotheses: 1) Information regarding low (innocuous) and high-pressure distention of the stomach and duodenum is conveyed to the NST predominantly by vagal primary afferents. The primary afferents can be classified according to the region stimulated (stomach and/or duodenum) and the response to the intensity of the stimulus (low threshold [LT], wide dynamic range [WDR], and high threshold [HT]). 2) NST neurons can also be classified according to the region stimulated the response (LT, WDR, HT). 3) The three distinct groups of NST neurons transmit information to specific regions of the central nervous system. The LT neurons project to the vagal motor nucleus. The main targets for WDR neurons are the sites involved in pain perception and the behavioral response to pain. The majority of HT neurons project to sites involved in pain control. 4) The excitation of NST neurons by low- pressure distention is due to glutamate release whereas the response to high-pressure distention is due to the release of both glutamate and substance P. We will test these hypotheses with four specific aims that employ a combination of extra- and intracellular recording and labeling techniques, electrical forebrain stimulation and Picospritzer delivery of neurotransmitter antagonists to NST neurons. The resultant data will enhance our knowledge of the neural circuits responsible for the receipt, integration and transmission of visceral pain and ultimately lead to new strategies to alleviate abdominal pain.
