Neurons located in the wall of the bowel project out of the gut to innervate targets in the pancreas. The majority of these entero-pancreatic fibers terminate on intrapancreatic ganglia. When enteric neurons are stimulated, neurons in pancreatic ganglia, as well as the islet and acinar cells they innervate, are activated. Retrograde tracing studies, involving the injection of Fluoro-Gold (FG) into the pancreatic parenchyma, have established that the enteric neurons that project to the pancreas are located in the myenteric plexus of the duodenum and stomach. A subset of these entero-pancreatic neurons must be cholinergic, because enteric activation of pancreatic cells can be antagonized by hexamethonium. An additional subset is serotonergic, since injections of FG into the pancreas specifically label serotonergic neurons in the myenteric plexus of the bowel. At present, the role of the entero-pancreatic innervation is unknown. In order to investigate what this role may be, it is important to (i) identify the anatomical components of entero-pancreatic reflex pathways, (ii) to ascertain the types of stimuli responsible for the physiological activation of these reflexes, (iii) to determine the respective roles of the serotonergic and cholinergic constituents of the entero-pancreatic innervation, and (iv) to establish the effects on pancreatic exocrine and endocrine secretion of physiological activation of entero-pancreatic reflexes. Acute pancreatitis is an often devastating medical condition. Although it is often associated with alcoholism, biliary tract disease, or surgery, acute pancreatitis also arises idiopathically. The pathogenesis of neither the disease associated with other conditions, nor that of the idiopathic variety is known. In addition to its acute form, pancreatitis also occurs chronically and causes considerable morbidity. Treatment consists of trying to put the pancreas to rest, but other than for analgesics, no specific pharmacological means exist to treat pancreatitis. The extent to which the enteric innervation of the pancreas influences the generation or course of pancreatitis has never been investigated and thus is unknown; however, in view of the powerful action the entero-pancreatic innervation exerts on exocrine pancreatic activity, it is likely that the entero-pancreatic innervation is an important factor in pancreatic disease. If so, then the entero- pancreatic innervation may also be a target for drugs that affect the induction or progress of pancreatitis. An NIH Research and Career Development Award would enable me to devote my time to research, and analyze the entero-pancreatic innervation, particularly its serotonergic component. During the period of this award, I will devote 90% of my time to research. The award will also have the major effect of establishing me as an independent investigator, which is critical in achieving tenure at Columbia.
