Nausea and vomiting (emesis) commonly occur in association with cancer chemo- and radiation therapy, post-operative recovery, motion and space sickness, pregnancy, and various diseases including AIDS. The long-term goal of this project is to determine the neural mechanisms that produce vomiting under various conditions. Increased understanding of the neural circuitry involved, together with a growing knowledge of neurotransmitter receptor subtypes, should lead to improved pharmaceutical countermeasures. Studies will be conducted using the """"""""fictive vomiting"""""""" experimental model, which is characterized by a series of bursts of coactivation of diaphragmatic (phrenic) and abdominal motor nerves in decerebrate, paralyzed cats. The specific objectives are to investigate neural inputs that trigger or inhibit vomiting and the central neuronal circuitry that produces vomiting, including pre-motor neurons involved in generating the pattern of respiratory muscle activation critical for the motor act of vomiting. The potential for gastric vagal, hepatic vagal, and splanchnic inputs to trigger vomiting will be determined, as will possible interactions between vagal and splanchnic inputs and the importance of the area postrema in mediating vagal-induced vomiting. Preliminary studies indicate that the medullary nucleus of the solitary tract (NTS) may play an important role as an integrating site for different emetic inputs. NTS neurons will be tested to determine if they receive convergent excitation from different inputs capable of triggering vomiting, including the area postrema chemoreceptor emetic trigger zone and abdominal vagus and vestibular nerves, as well as in response to various emetic drugs such as the cancer chemotherapeutic agent cisplatin. Vomiting elicited by a broad range of inputs can be inhibited by unknown afferents in the cervical vagus nerve. The source of this inhibitory input will be determined, as will the possibility that its anti-emetic effects are mediated by inhibition of NTS neurons that are excited by convergent emetic inputs. Abdominal and internal intercostal expiratory motoneurons receive central respiratory drive from bulbospinal pre-motor expiratory neurons located in the caudal ventral respiratory group (VRG). During vomiting, caudal VRG expiratory neurons fire in two distinct patterns, which are appropriate to drive abdominal and internal intercostal motoneurons that fire out of phase with each other during vomiting. Intracellular recordings from caudal VRG expiratory neurons will determine the role of phasic inhibitory puts in producing these two discharge patterns. In addition, a search will be conducted for VRG neurons that may provide the still unknown source of excitatory drive to phrenic and co-active external intercostal motoneurons during vomiting. Finally, a study will be made of the contribution to the control of the upper airway during vomiting by a projection from neurons in the nucleus retroambigualis (in the caudal VRG) to the nucleus ambiguous, which contains motoneurons innervating upper airway musculature.
