Investigation into the µ opioid receptor role in an experimental model of mesenteric ischemia/reperfusion.

Abstract

ABSTRACT Intestinal ischemia is a clinical gastrointestinal emergency associated with high morbidity and mortality. Aim of this study was to investigate whether activation of µ opioid receptors (µORs) protects from the injury induced by intestinal ischemia and reperfusion. Ischemia was induced by occlusion of the superior mesenteric artery (45 min) and followed by reperfusion (5hours) (I/R). Sham Operated (SO) and normal (N) mice served as controls. Each group received subcutaneously: (1) saline solution; (2) the µOR selective agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (0.01 mg kg−1); (3) DAMGO and the selective µOR antagonist [H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2] (CTAP) (0.1 mg kg−1) or (4) CTAP alone. Compared to SO, I/R induced intestinal inflammation as indicated by the histological damage and the significant increase in myeloperoxidase (MPO) activity (index of tissue neutrophil accumulation). Treatment with DAMGO significantly reduced tissue damage and MPO activity in I/R and these effects were reversed by CTAP. Significant increase in levels of the inflammatory cytokine TNF-a and IL-10 mRNA was detected in I/R mice compared to SO. DAMGO significantly reduced TNF-a mRNA levels in I/R, effect that was abolished by CTAP, but did not modify IL-10 mRNA levels. µOR mRNA levels were comparable in I/R, SO and N mice. There was a significant delay in gastrointestinal transit in both I/R and SO compared to N mice, which was not affected by DAMGO administration. In summary, this investigation shows that exogenous activation of µORs plays a protective role in our experimental model of mesenteric I/R in mice. Indeed, µOR activation is able to reduce the intestinal damage induced by I/R, through a mechanism that appears to be in part mediated by TNF-a.