Ligand-induced μ opioid receptor internalization in enteric neurons following chronic treatment with the opiate fentanyl
ABSTRACT Morphine differs from most opiates 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 β-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 after 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's 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 or induce changes in intracellular trafficking proteins, as observed with prolonged activation of μORs with a poorly internalizing agonist such as morphine. Cellular adaptations induced by chronic opiate treatment might be ligand dependent and vary with the agonist efficiency to induce receptor internalization. © 2013 Wiley Periodicals, Inc.
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ABSTRACT: Opiate analgesics such as morphine are often used for pain therapy. However, long-term use of these drugs may develop antinociceptive tolerance and dependence. It was found that μ-opioid receptor (MOPr) could interact with δ-opioid receptor (DOPr), and morphine antinociceptive tolerance could be reduced by blockage of DOPr. Recent studies show that MOPr and DOPr are co-expressed in a considerable population of peptidergic small neurons in the dorsal root ganglion. The MOPr/DOPr interaction in the nociceptive afferents is facilitated by the stimulus-induced cell-surface expression of DOPr, and contributes to morphine tolerance. Further analysis on the molecular, cellular and neural circuit mechanisms for regulating the trafficking and interaction of opioid receptors and related signaling molecules in the pain pathway would help to understand the mechanism of opiate analgesia and improve pain therapy.British Journal of Pharmacology 02/2014; 172(2). DOI:10.1111/bph.12653 · 4.99 Impact Factor
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ABSTRACT: Opioid receptors (OR) are part of the class A of G-protein coupled receptors and the target of the opiates, the most powerful analgesic molecules used in clinic. During a protracted use, a tolerance to analgesic effect develops resulting in a reduction of the effectiveness. So understanding mechanisms of tolerance is a great challenge and may help to find new strategies to tackle this side effect. This review will summarize receptor-related mechanisms that could underlie tolerance especially receptor desensitization. We will focus on the latest data obtained on molecular mechanisms involved in opioid receptor desensitization: phosphorylation, receptor uncoupling, internalization, and post-endocytic fate of the receptor.Frontiers in Pharmacology 01/2014; 5:280. DOI:10.3389/fphar.2014.00280