Background & Aims-The μ opioid receptor (μOR) undergoes rapid endocytosis following acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of μOR affects morphine's ability to induce receptor endocytosis in enteric neurons.

Background-μ opioid receptors (μORs) are expressed by neurons and inflammatory cells and mediate immune response. We tested whether activation of peripheral μORs ameliorates the acute and delayed phase of colitis.

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) and followed by reperfusion (5 hours). 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, index of tissue neutrophil accumulation. TNF-α and IL-10 mRNA levels were also increased in I/R mice compared to 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 and gastrointestinal transit. DAMGO effects are receptor-mediated and are likely due to activation of peripheral µORs since 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 pro-inflammatory cytokine, TNF-α. Reduction of acute inflammation might prevent I/R complications, including motility impairment, which develop at a later stage of reperfusion and are likely due to inflammatory cell infiltrates.

Morphine differs from most opiates for its poor ability to internalize μ opioid receptors (μORs). However, chronic treatment with morphine produces adaptational changes at the dynamin level, which enhance the efficiency of acute morphine stimulation to promote μOR internalization in enteric neurons. This study tested the effect of chronic treatment with fentanyl, a μOR internalizing agonist, on ligand-induced endocytosis and the expression of the intracellular trafficking proteins, dynamin and ß arrestin, in enteric neurons using organotypic cultures of the guinea pig ileum. In enteric neurons from guinea pigs chronically treated with fentanyl, μOR immunoreactivity was predominantly at the cell surface following acute exposure to morphine with a low level of μOR translocation, slightly higher than in neurons from naïve animals. This internalization was not due to morphine direct effect because it was also observed in neurons exposed to medium alone. By contrast, D-Ala2-N-Me-Phe4-Gly-ol5-enkephalin (DAMGO), a potent μOR-internalizing agonist, induced pronounced and rapid μOR endocytosis in enteric neurons from animals chronically treated with fentanyl or from naïve animals. Chronic fentanyl treatment did not alter dynamin or β-arrestin expression. These findings indicate that prolonged activation of μORs with an internalizing agonist such as fentanyl does not enhance the ability of acute morphine to trigger μOR endocytosis nor induces changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by opiate chronic treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization.

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