One out of three Americans will suffer a bowel disorder such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD) at some point in their lives. These disorders result in significant costs to society, a combined total of approximately $30 billion annually. The major complaints in these patients are changes in bowel movements and pain. Current hypotheses support that changes in peristalsis and visceral hypersensitivity present in models of bowel disorders may be linked to the N-methyl-D-aspartate (NMDA) receptors. We previously reported the expression of the NMDA receptor NR1 subunit splice variants in the rat myenteric plexus before and after inflammation. We found that on untreated animals the NR1 splice variants present are NR1-001 and NR1-000. After inflammation the expression of NR1 was notably increased. Moreover, the expression of splice variants NR1-011 and NR1-111 was also increased 14 days after inflammation. We hypothesize that the changes in NMDA receptor expression/activity could affect colonic contractibility, which then induces pain. In this proposal we plan to use a rat model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) to characterize the effect of inflammation and different NMDA ligands in colon contractibility using a multi-channel isolated tissue bath system. We will evaluate the enteric NMDA receptor subtypes present on inhibitory VIP/NOS-containing motor neurons before and after inflammation with multiple-labeling immunohistochemistry using specific antibodies targeting the different NMDA receptors subtypes, VIP and NOS. Finally we will analyze the effect of NMDA receptors' agonists and antagonists in the release of vasoactive intestinal peptide (VIP) and nitric oxide (NO) using specific Elisa and fluorometric assays before and after inflammation. We predict that after the TNBS-induced inflammation the enteric NMDA receptors influence the release of VIP and NO, altering colonic contractibility which could explain the associated visceral hypersensitivity found in animal models of bowel disorders and reported by patients. Because disturbances in peristalsis are the major factors affecting the quality of life in patients with bowel disorders, it is critical that we increase our knowledge of NMDA receptor structural/functional changes in the enteric nervous system (ENS). The identification of the NMDA receptors in the enteric nervous system could lead to the development of drugs that selectively modulate bowel function. ? ? ?
| Del Valle-Pinero, Arseima Y; Sherwin, LeeAnne B; Anderson, Ethan M et al. (2015) Altered vasoactive intestinal peptides expression in irritable bowel syndrome patients and rats with trinitrobenzene sulfonic acid-induced colitis. World J Gastroenterol 21:155-63 |
