Peripheral Opioid Receptor Blockade Enhances Epithelial Damage in Piroxicam-Accelerated Colitis in IL-10-Deficient Mice.

Xavier Mas-Orea,Mehdi Benamar,Morgane Sebert,Camille Petitfils,Céline Deraison,Gilles Dietrich,Frederick Barreau,Abdelhadi Saoudi,Catherine Blanpied,Nicolas Cenac

doi:10.3390/ijms22147387

Abstract

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood–brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.

Highlights

Il-10-/- Mice Treated with Piroxicam Develop Colitis
-/mice fed standard chow diet containing for 10macroscopic days developed colitisIL-10 characterized by with a significant body weight loss
IL-10-/- the mice fed with dietcells free(virtually of piroxicam

Summary

Introduction

Even in the IL-10-deficient mouse model mimicking severe infantile Crohn’s disease associated with IL-10 loss of function, colitogenic CD4+ T lymphocytes conserve their analgesic activity [13]. These observations strengthen the rationale of a number of potential therapeutic strategies which propose to enhance or mimic immune-mediated endogenous opioid activity in chronic intestinal inflammatory diseases [14,15,16]. These therapeutic approaches aim at targeting opioid receptors in the periphery [17,18,19] and, for some of them, opioid receptors located within the inflamed tissue [1,20,21,22,23,24] or at reinforcing endogenous immune-derived opioid tone [25,26]

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Results

Conclusion