Protective role of μ opioid receptor activation in intestinal inflammation induced by mesenteric ischemia/reperfusion in mice.
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.
Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.
Francesca
F
Saccani
Laura
L
Anselmi
Ingrid
I
Jaramillo
Simona
S
Bertoni
Elisabetta
E
Barocelli
Catia
C
Sternini
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply / Q000473:pathology; D008643:Mesentery / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D017450:Receptors, Opioid, mu