Repeated Vagus nerve electrical stimulation alleviates constipation in a porcine model of opioid-induced constipation
Authors: Atmani Karim , Larauche Muriel , Han Xu , Chen Yan-Peng , Wagner Justin , Liu Wentai , Mulugeta Million 
Published: May 2024

Background: Chronic constipation (CC) is highly prevalent and affects approximately 15% of persons in the United States. Opioid-induced constipation (OIC) in particular, is a significant complication affecting up to 80% of non-cancer patients receiving opioids. Current treatments for CC suffer from adverse effects, poor compliance, and low effcacy. Progress in treatment of CC is hampered in part by the lack of studies in models of higher translational value and due to limited means to assess gut motility non-invasively. To palliate this lack of, we recently developed and validated a model of opioid-induced constipation in pigs using chronic administration of the mu-opioid agonist, loperamide[1]. Neuromodulation, of the autonomic nervous system, is now regarded as the future therapy for refractory diseases such as refractory OIC. Our previous work in naïve-anesthetized pigs indicate that acute electrical stimulation of the celiac branch of the Vagus nerve (CBVN) can increase colonic motility. It is, however, unknown whether repeated CBVN stimulation (R-CBVNS) in conscious pigs can relieve chronic constipation induced by repeated opioid exposure. Aims: To evaluate the effect of R-CBVNS in a porcine model of opioid-induced constipation induced by chronic administration of loperamide. Methods: Female minipig Yucatan (35-50 kg, 5-7 months) were surgically equipped with a cuff electrode around the CBVN and a cecal cannula. Fourteen days later, pigs received daily oral administration of loperamide at 0.2, 0.4 or 3 mg/kg/day in regular diet mixed with palatant (bananas, marshmallows or yogurt mixed with honey) for 14-30 days. After 2 days of loperamide, the effect of concurrent R-CBVNS (30 min/day, 2 Hz, 1 mA, 300 us, 30s on/90s off) was tested on chronic OIC. The intracolonic pressure signals were collected on day 2, 7 and 14, by manometric probes placed in the proximal (pc) and distal colon (dc) with a sampling frequency of 100Hz in awake pigs fitted with chronic cecal cannulas. The long-term effects of R-CBVNS was also tested on the highest dose of loperamide by monitoring motility on day 21 and day 28, 1 and 2 weeks respectively after discontinuing R-CBVNS. In the distal colon, four probes were inserted through the anus and aligned at 10, 13, 16, and 19 cm proximal to the anal verge, denoted as D10, D13, D16, D19. In the proximal colon, four probes were inserted about 10, 13, 16, and 19 cm below the ceco-colic junction, denoted as P10, P13, P16, and P19. Analysis of the intracolonic pressure signals was performed by custom scripts developed in the MATLAB version 2020b. The colon luminal pressure spectral analysis, signal power spectrum density as well as peak frequency and contraction bursts were characterized. Defecation response and stool water content changes (SWC, Bristol scale) were monitored. Results: Loperamide altered the power of dominant manometric contraction frequency band (2-7cpm) increasing it in the pc but reducing it in the dc suggesting colon-region specific responses (0.4 and 3mg/kg/day). R-CBVNS in pigs treated with 0.2, 0.4 or 3 mg/kg/day (for 14 days) increased primarily the proximal colon contraction frequency power during and post stimulation period. The increase in the proximal colon contraction power was mainly seen in the pig colon dominant frequency band (2-6 cpm). The effect of R-CBVNS was less apparent on distal colon motility. R-CBVNS improved stool shape and tended to increase stool water content, when compared to loperamide without concurrent stimulation. Moreover, after 2 weeks of R-CBVNS, the effect lasted one week after the stimulation protocol ended. Conclusions: OIC in pigs is characterized by delayed GI transit and decreased stool water content, alterations of colonic motility patterns including selective suppression of 5-6 cpm peak frequency while inducing 3 cpm peak akin to that reported in some CC patients. R-CBVNS demonstrates its effectiveness in alleviating chronic constipation in a swine model of OIC via restoring primary colonic functions, with a quasi-return of basal motility, but also probably through a pro-secretory effect as evidenced by an increase in stool water content. Reference: 1. Atmani, K., et al., A porcine model of opioid-induced constipation: colon motility characterization and evidence for intestinal opioid receptor modulation. Physiology, 2023. 38(S1): p. 5734528. Supported by NIH SPARC OT2-OD024899. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.