Intestinal ischemia is a clinical emergency with high morbidity and mortality. We investigated whether activation of μ opioid receptor (μOR) protects from the inflammation induced by intestinal ischemia and reperfusion (I/R) in mice. Ischemia was induced by occlusion of the superior mesenteric artery (45 min), followed by reperfusion (5 hr). 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. I/R induced intestinal inflammation as indicated by histological damage and the significant increase in myeloperoxidase (MPO) activity, an index of tissue neutrophil accumulation. Tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) mRNA levels were also increased in I/R mice compared with SO. DAMGO significantly reduced tissue damage, MPO activity, and TNF-α mRNA levels in I/R, and these effects were reversed by CTAP. By contrast, DAMGO did not modify IL-10 mRNA levels or gastrointestinal transit. DAMGO's effects are receptor mediated and likely are due to activation of peripheral μORs, because it does not readily cross the blood-brain barrier. These findings suggest that activation of peripheral μOR protects from the inflammatory response induced by I/R through a pathway involving the proinflammatory cytokine TNF-α. Reduction of acute inflammation might prevent I/R complications, including motility impairment, which develop at a later stage of reperfusion and likely are due to inflammatory cell infiltrates.