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The Journal of Neuroscience, December 1, 2002, 22(23):10192-10200
Chronic Morphine Treatment Inhibits Opioid Receptor
Desensitization and Internalization
Daniela A.
Eisinger,
Hermann
Ammer, and
Rüdiger
Schulz
Institute of Pharmacology, Toxicology and Pharmacy, University of
Munich, D-80539 Munich, Germany
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 µ-OR
(MOR) uncoupling and internalization, two regulatory mechanisms
contributing to rapid desensitization of OR function. Chronic morphine
treatment (1 µM; 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-Ala2,
D-Leu5]enkephalin (DADLE) and etorphine
to desensitize opioid-stimulated [35S]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-protein-coupled receptors, such as the m4-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.
Key words:
-opioid receptor; chronic morphine; receptor
desensitization; receptor internalization; -arrestin; MAP kinase
Copyright © 2002 Society for Neuroscience 0270-6474/02/222310192-09$05.00/0
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