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NEUROREGULATION AND MOTILITY

Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function

Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Departments of ¹Internal Medicine and ²Neuroscience and Cell Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas

Submitted 19 December 2008 ; accepted in final form 2 April 2009

Chronic stress precipitates or exacerbates the symptoms of functional bowel disorders, including motility dysfunction. The cellular mechanisms of these effects are not understood. We tested the hypothesis that heterotypic chronic stress (HeCS) elevates the release of norepinephrine from the adrenal medulla, which enhances transcription of the gene-regulating expression of Ca_v1.2 (L-type) channels in colonic circular smooth muscle cells, resulting in enhanced colonic motor function. The experiments were performed in rats using a 9-day heterotypic chronic stress (HeCS) protocol. We found that HeCS, but not acute stress, time dependently enhances the contractile response to ACh in colonic circular smooth muscle strips and in single dissociated smooth muscle cells, the plasma levels of norepinephrine and the mRNA and protein expressions of the _1C subunit of Ca_v1.2 channels. These effects result in faster colonic transit and increase in defecation rate. The effects of HeCS are blocked by adrenalectomy but not by depletion of norepinephrine in sympathetic neurons. The inhibition of receptors for glucocortocoids, corticotropin-releasing hormone or nicotine also does not block the effects of heterotypic chronic stress. Norepinephrine acts on - and β₃-adrenergic receptors to induce the transcription of _1C subunit. We conclude that HeCS alters colonic motor function by elevating the plasma levels of norepinephrine. Colonic motor dysfunction is associated with enhanced gene transcription of Ca_v1.2 channels in circular smooth muscle cells. These findings suggest the potential cellular mechanisms by which heterotypic chronic stress may exacerbate motility dysfunction in patients with irritable bowel syndrome.

corticotropin-releasing hormone; corticosterone; enteric neurotransmitters; smooth muscle