A porcine model of opioid-induced constipation: colon motility characterization and evidence for intestinal opioid receptor modulation

Abstract

Background: About 41-81% of non-cancer patients receiving opioid analgesics for chronic pain develop opioid induced constipation (OIC). Response of OIC to currently available first line therapies is inadequate and prescription drugs come with side effects. Knowledge on the specific effects of chronic opioids on gut motility mechanisms involved isincomplete. Goal: Develop OIC model and characterize gut motility and colonic opioid receptor (OR) modulation in a high translational value porcine model. Methods: The influence of loperamide, a preferential m-OR agonist, on colon motility, intestinal transit, fecal water content (FWC) and colonic OR expression was studied in Yucatan pigs (adult, male and female) naïve or fitted with a chronic cecal cannula. Loperamide was given orally at 0.2, 0.4, and 3 mg/kg/day for 15-30 days in regular diet mixed with palatants (bananas, marshmallows or yogurt mixed with honey). Manometry recordings of the proximal (pc) and distal (dc) colon motility were done using Millar pressure probes placed in each region (4-5 probes, sensors 3cms apart) in awake pigs with chronic cecal cannulas (n=3). In the same pigs, we tested the effect of the luminal stimulator VibrabotTM (30 min or 18 h) on colon motility and FWC under control and loperamide-induced constipation (1, 2 or 3 days). VibrabotTM was inserted into the proximal colon through the cecal cannula. Colonic tissues were collected and mOR expression was assessed using RNAscope. Results: Colon contraction frequency analysis shows region-specific differential effects of loperamide with an increased activity in the proximal and reduced activity in the distal colon. At the highest dose, it causes selective suppression of 5 cpm peak frequency while inducing 3 cpm peak. Loperamide (0.4mg/kg/day) reduces FWC (69.5±0.9 vs 75.9±0.9, p<0.001), and VibrabotTM stimulation (18-hours) reverses the loperamide-induced decreased FWC (74.7±3.3 vs 69.5±0.0.9). ORs are expressed differentially in the proximal vs distal colon (3.5±0.5 vs 4.6±0.8 dot/cell). Loperamide (0.4 or 3mg/kg/day, 30 days) induces an upregulation of colonic mOR expression (3.1±0.8 vs 4.4±1.2 & 4.3±0.6 dot/cell,). Conclusions: Loperamide in pigs causes constipation as shown by decreased FWC, differential effects on proximal vs distal colon contraction frequency power, with an overall inhibition of motility, while increasing m OR expression in both proximal and distal colon. Whether the differential expression of m OR in the different regions and layers of the colon contribute to the regional differences in motility needs further studies. Prolonged luminal stimulation of the colon with VibrabotTM reverses loperamide-induced decreased FWC. We established a model of OIC in pigs that has high face and construct validity as it is characterized by decreased FWC and alterations of colonic motility patterns akin to that reported in some chronic constipation patients. Supported by NIH SPARC OT2-OD024899. This is the full abstract presented at the American Physiology Summit 2023 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.