Autonomic regulation of digestive function during stress: Role of brain peptides

Abstract

Various stressors impacts on the gut function resulting in the inhibition of gastric and stimulation of colonic motor function and increased visceral pain to colorectal distention (CRD). Stress activates brain CRF system that encompasses the peptide corticotropin releasing factor (CRF), and related urocortin (Ucn ) 1, Ucn 2 and Ucn 3 and two distinct CRF1 and CRF2 receptors. CRF has preferential affinity toward the CRF1 receptor while Ucn 1 has equal affinity to both receptors and Ucn 2 and Ucn 3 are selective ligands for CRF2. Intracisternal injection of CRF, Ucn 1 and Ucn 2 inhibit gastric emptying of liquid or solid meal through CRF2 receptors modulating vagal and sympathetic outflow to the stomach (decrease vagal efferent and increased sympathetic activity) in rats and mice. Various stressors (ether, partial restraint, peritoneal irritation, swim stress, abdominal surgery, interleukins) induce 30–80% inhibition of gastric emptying that is prevented by central injection of CRF antagonists. Only acute cold stress exposure stimulates gastric motor function through activation of medullary thyrotropin releasing hormone (TRH) cell bodies in the raphe pallidus, raphe obscurus and parapyramidal region that project to the dorsal motor nucleus (DMN). Activation of TRH1 receptor on DMN neurons by TRH results in stimulation of gastric vagal efferent discharges, activation of gastric myenteric cholinergic neurons and related increase of gastric secretion (acid, pepsin, histamine, serotonin, mucus) and gastric motor function ( motility and emptying) in rats. With regards to the colon, various stressors (partial restraint, water avoidance, open field test) stimulates propulsive motor function in rodents that is mimicked by central injection of CRF into the cerebrospinal fluid, paraventricular nucleus of the hypothalamus (PVN) or locus coeruleus/subcoeruleus (LC/SC) in rats. Water avoidance activates neurons in the PVN, LC/SC, sacral spinal parasympathetic nucleus and colonic myenteric ganglia resulting in increased parasympathetic outflow and cholinergic enteric neurons stimulating colonic motility, transit and defecation. Central injection of CRF antagonists reduced by 50% brain neuronal activation selectively in the PVN and LC and defecation response to water avoidance and blocked the induction of rapid distal colonic transit in rats. The stress-colonic stimulatory response is mediated by CRF1 receptors as shown by pharmacological approaches using selective CRF1 antagonists and CRF1 knockout mice and is also involved in visceral hypersensitivity to CRD induced stress. These studies provide insight to specific brain peptidergic pathways namely the CRF system recruited by stressors that impacts on digestive function through autonomic-gut enteric nervous system interactions.