Anti-inflammatory properties of the μ opioid receptor support its use in the treatment of colon inflammation
David Philippe, … , Brigitte L. Kieffer, Pierre Desreumaux
David Philippe, … , Brigitte L. Kieffer, Pierre Desreumaux
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1329-1338. https://doi.org/10.1172/JCI16750.
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Article Neuroscience

Anti-inflammatory properties of the μ opioid receptor support its use in the treatment of colon inflammation

Abstract

The physiologic role of the μ opioid receptor (MOR) in gut nociception, motility, and secretion is well established. To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4+ T cells in mice. This therapeutic effect was almost completely abolished by concomitant administration of the opioid antagonist naloxone. Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring 3 days after TNBS administration. The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD). These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD.

Authors

David Philippe, Laurent Dubuquoy, Hervé Groux, Valérie Brun, Myriam Tran Van Chuoï-Mariot, Claire Gaveriaux-Ruff, Jean-Frédéric Colombel, Brigitte L. Kieffer, Pierre Desreumaux

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MOR regulates expression of inflammatory and immunoregulatory cytokines ...
MOR regulates expression of inflammatory and immunoregulatory cytokines in the colon. (a and b) Quantification of TNF-α, IL-4, and IFN-γ mRNA concentrations in the healthy colon of (a) Balb/c mice receiving vehicle (C) for 8 days, the MOR agonist DALDA (D) for 8 days, or the opioid antagonist NM administered subcutaneously for 10 consecutive days and in colon of (b) adult MOR–/– mice and their wild-type littermates. (c) Quantification of inflammatory cytokine levels four days after treatment in the colon of Balb/c mice receiving vehicle only (Control), TNBS only, or DALDA followed 4 days later by TNBS. (d) Quantification of inflammatory cytokine levels in the colon 4 weeks after T cell transfer in control SCID mice reconstituted with both CD4+CD45RBlo and CD45RBhi T cells (Hi + Lo) and in SCID mice with colitis reconstituted with CD4+CD45RBhi T cells without any treatment (Hi) or after subcutaneous administration of DALDA (10–2 mg/kg/d) (Hi + D) or DAMGO (10–3 mg/kg/d) (Hi + Do). The number of mice and statistical significance are indicated and results are expressed as mean ± SEM.