Chronic Morphine Treatment Inhibits Opioid Receptor Desensitization and Internalization

Abstract

Chronic opioid receptor (OR) activation by morphine causes distinct cellular adaptations responsible for the development of tolerance. The present study examines the effect of chronic morphine exposure on the ability of high-efficacy agonists to mediate ␦-OR (DOR) and -OR (MOR) uncoupling and internalization, two regulatory mechanisms contributing to rapid desensitization of OR function. Chronic morphine treatment (1 M; 72 hr) of DOR carrying neuroblastoma x glioma (NG108-15) hybrid cells, a prototypical model system frequently used to study cellular aspects of opioid tolerance, completely blocked the capacity of [D-Ala 2 , D-Leu 5 ]enkephalin (DADLE) and etorphine to desensitize opioid-stimulated [ 35 S]GTP␥S binding and to mediate DOR internalization. Similar findings were obtained on stably DOR-and MOR-transfected human embryonic kidney (HEK) 293 cells. Chronic morphine treatment also heterologously impaired agonist regulation of non-opioid G-proteincoupled receptors, such as the m 4 -muscarinic acetylcholine receptor and the brain-type cannabinoid receptor. As a possible underlying mechanism, we found that chronic morphine treatment completely blocked agonist-induced redistribution of ␤-arrestin1 in both NG108-15 and stably MOR-transfected HEK293 cells. Moreover, attenuation of ␤-arrestin1 function appears to depend on persistent stimulation of MAP kinase activity during the course of chronic morphine treatment, because coincubation of the cells together with the MAP kinase blocker PD98059 fully restored ␤-arrestin1 translocation and receptor internalization. These results demonstrate that chronic morphine treatment produces adaptational changes at the ␤-arrestin1 level, which in turn attenuates agonist-mediated desensitization and internalization of G-protein-coupled receptors.

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

“…ARRB1 regulates the desensitization of numerous GPCRs including OPRM1, D1 and D2 dopamine receptors and emerging evidence has demonstrated that ARRB1 functions as a scaffold protein that links GPCRs to intracellular signaling, such as MAPK and as a transcription factor that translocates to the nucleus (16,17). A recent study showed that chronic morphine treatment blocked the agonist-induced redistribution of ARRB1 in stably OPRM1-transfected HEK293 cells through the persistent stimulation of MAPK activity and the authors concluded that chronic morphine treatment produces adaptational changes at the ARRB1 level (18). These observations and our findings suggest that the drug response of PBLs to morphine mediates the down-regulation of ARRB1 expression during morphine treatment and reflects the overall cellular response to opioid signaling in an individual.…”

Serine 363 of the δ-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands

“…Recently, agonist-specific desensitization of ERK signaling pathway has been reported for the OR (Eisinger et al, 2002;Hong et al, 2009). In addition, differential kinetic patterns of ERK activation by individual OR agonists have also been observed (Eisinger and Schulz, 2004;Audet et al, 2005).…”

“…ERK1/2 activated by etorphine is quite transient, whereas ERK1/2 activated by morphine is quite persistent (Eisinger and Schulz, 2004). Moreover, such different patterns of ERK activation induced by morphine and etorphine have been linked to their ability to differently desensitize and internalize OR (Eisinger and Schulz, 2004;Eisinger et al, 2002;Audet et al, 2005). However, the molecular mechanisms underlying this differential regulation of ERK activation by distinct agonists remain unclear.…”

“…S2). It has also been reported that differential temporal patterns of ERK activation can be detected upon activation of the ORs by distinct agonists (Eisinger et al, 2002;Eisinger and Schulz, 2004). However, the role of Ser363 in the C-terminal for the OR adoption of distinct pathways to activate ERK remains to be elucidated.…”

Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

“…The results of the study showed that DOR-eGFP internalization is strongly correlated with receptor phosphorylation and uncoupling from G-proteins [38] . Chronic morphine treatment produces adaptive changes at the β-arrestin 1 level, which in turn attenuate the agonist-mediated desensitization and internalization of GPCRs [39] . Patwardhan et al have shown that peripheral activation of primary afferent nociceptors with bradykinin [40] or trypsin [41] enhances both the targeting of DORs to the cell surface and receptor competence.…”