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[摘要]：BACKGROUND & AIMS: The mu opioid receptor (mu OR) undergoes rapid endocytosis after acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of mu OR affects morphine's ability to induce receptor endocytosis in enteric neurons. METHODS: We compared the effects of morphine, a poor mu OR-internalizing opiate, and (D-Ala2,MePhe4,Gly-ol5) enkephalin (DAMGO), a potent mu OR-internalizing agonist, on mu OR trafficking in enteric neurons and on the expression of dynamin and beta-arrestin immunoreactivity in the ileum of guinea pigs rendered tolerant by chronic administration of morphine. RESULTS: Morphine (100 mu mol/L) strongly induced endocytosis of mu OR in tolerant but not naive neurons (55.7% +/- 9.3% vs 24.2% +/- 7.3%; P < .001) whereas DAMGO (10 mu mol/L) strongly induced internalization of mu OR in neurons from tolerant and naive animals (63.6% +/- 8.4% and 66.5% +/- 3.6%). Morphine-or DAMGO-induced mu OR endocytosis resulted from direct interactions between the ligand and the mu OR because endocytosis was not affected by tetrodotoxin, a blocker of endogenous neurotransmitter release. Ligand-induced mu OR internalization was inhibited by pretreatment with the dynamin inhibitor, dynasore. Chronic morphine administration resulted in a significant increase and translocation of dynamin immunoreactivity from the intracellular pool to the plasma membrane, but did not affect beta-arrestin immunoreactivity. CONCLUSIONS: Chronic activation of mu ORs increases the ability of morphine to induce mu OR endocytosis in enteric neurons, which depends on the level and cellular localization of dynamin, a regulatory protein that has an important role in receptor-mediated signal transduction in cells. |
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