title: Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat.
abstract: Evidence to date suggests that stress-induced exacerbation or relapse of intestinal inflammation in inflammatory bowel disease requires both activation of the autonomic nervous system and the activation of the immune system by the presence of previously encountered luminal antigens. The aim of the present study was to further explore these associations and to determine the role of the autonomic nervous in modulating the intestinal inflammatory response to stress. Rats healed from an initial dinitrobenzene sulfonic acid-induced colitis were given a non-colitic dose of dinitrobenzene sulfonic acid (dissolved in saline) or 0.9% saline intra-rectally and then subjected to restraint stress. Cardiac sympathovagal balance was assessed by power spectral analysis of heart rate variability data collected from telemetric electrocardiogram recordings before, during and post stress. Only rats that were stressed and received dinitrobenzene sulfonic acid showed an inflammatory relapse characterized by significant macroscopic damage and elevated myeloperoxidase activity associated with a significant infiltration of mucosal and submucosal T lymphocytes. No difference in inflammatory markers was observed in animals that received intra-rectal saline and restraint stress. Rats subjected to stress and intra-rectal dinitrobenzene sulfonic acid demonstrated an increase in sympathetic activity with a nearly four fold increase in LF:HF ratio during stress and a significant increase in heart rate. Shortly after cessation of stress, the LF:HF ratio decreased significantly, returning to baseline levels, however the heart rate remained significantly elevated over baseline levels following stress, but decreased to a level that was significantly lower than during stress. The stress/dinitrobenzene sulfonic acid-induced relapses were preventable by pre-treating rats with hexamethonium (a nicotinic cholinergic ganglion blocking agent) or the co-administration of atropine (a muscarinic cholinoceptor antagonist) and bretylium (a noradrenergic ganglion blocking agent), but was not prevented when either atropine or bretylium were administered alone. This study utilizes an established model of chemically induced colitis that when integrated with stress results in relapsing inflammatory bowel disease. Moreover, this study demonstrates that noradrenergic and cholinergic neural pathways mediate the stress response critical for the relapse of colitis.
authors.affiliation: Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Saunders
authors.forename: Paula
authors.initials: P
authors.lastname: Miceli
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Pinto
authors.forename: Gervais
authors.initials: G
authors.lastname: Tougas
authors.forename: Markad
authors.initials: M
authors.lastname: Kamath
authors.forename: Kevan
authors.initials: K
authors.lastname: Jacobson
mesh_terms: D000208:Acute Disease; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D017776:Autonomic Pathways / Q000503:physiopathology*; D001950:Bretylium Tosylate / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D003106:Colon / Q000473:pathology; D018738:Hexamethonium / Q000494:pharmacology; D007150:Immunohistochemistry; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000503:physiopathology*; D010276:Parasympatholytics / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013565:Sympatholytics / Q000494:pharmacology; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D017252:CD3 Complex; D018733:Nicotinic Antagonists; D010276:Parasympatholytics; D013565:Sympatholytics; D018738:Hexamethonium; D001950:Bretylium Tosylate; D001285:Atropine; D009195:Peroxidase