Auricular Vagal Nerve Stimulation Improves Constipation by Enhancing Colon Motility via the Central-Vagal Efferent Pathway in Opioid-Induced Constipated Rats

Abstract

Constipation and opioid-induced constipation (OIC) are common with limited treatment options. We investigated whether a noninvasive method of auricular vagal nerve stimulation (aVNS) could be used for treating OIC and explored its potential mechanisms and neural pathways in a rodent model of OIC. Sprague-Dawley were chronically implanted with one pair of auricular electrodes for aVNS. Sixteen rats were treated with loperamide for a week while another 16 rats received bilateral vagotomy, then randomly treated with aVNS or sham-aVNS for a week. In addition, eight normal rats were implanted with a polyethylene catheter in the proximal colon for assessing whole colon transit. 1) The number of fecal pellets and water content in feces increased after aVNS, compared with sham-aVNS. 2) aVNS accelerated colon transit and whole gut transit, compared with sham-aVNS. 3) In colon tissues, aVNS increased the protein expression of choline acetyltransferase, glial cell line-derived neurotrophic factor and the c-kit expression in myenteric interstitial cells of Cajal but decreased the protein expression of neural nitric oxide synthase (p < 0.05 for all, vs. sham-VNS). 4) The prokinetic effects of aVNS were abolished by both subdiaphragmatic vagotomy and atropine. 5) aVNS increased the c-fos expression in both nucleus tractus solitarius and dorsal motor nucleus of vagus, and increased vagal efferent activity (p < 0.05, vs. sham-VNS). aVNS improves OIC by enhancing colon motility and restoring enteric neural functions mediated via the central and vagal efferent pathway.