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The Journal of Neuroscience, October 1, 2001, 21(19):7598-7607
Prolonged Morphine Treatment Targets  Opioid Receptors to
Neuronal Plasma Membranes and Enhances -Mediated Antinociception
Catherine M.
Cahill1,
Anne
Morinville1, 2,
Mao-Cheng
Lee1,
Jean-Pierre
Vincent3,
Brian
Collier2, and
Alain
Beaudet1
1 Department of Neurology and Neurosurgery, Montreal
Neurological Institute, Montréal, Québec, Canada H3A 2B4,
2 Department of Pharmacology and Therapeutics, McGill
University, Montréal, Québec, Canada, H3G 1Y6, and
3 Institut de Pharmacologie Moléculaire et
Cellulaire, Centre National de la Recherche Scientifique,
Université de Nice, 06560 Valbonne, France
Opioid receptors are known to undergo complex regulatory changes in
response to ligand exposure. In the present study, we examined the
effect of morphine on the in vitro and in
vivo density and trafficking of  opioid receptors
(ORs). Prolonged exposure (48 hr) of cortical neurons in
culture to morphine (10 µM) resulted in a robust increase
in the internalization of Fluo-deltorphin, a highly selective
fluorescent OR agonist. This effect was µ-mediated because it was
entirely blocked by the selective µ opioid receptor antagonist
D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2
and was reproduced using the selective µ agonist fentanyl citrate.
Immunogold electron microscopy revealed a marked increase in the cell
surface density of ORs in neurons exposed to morphine, indicating
that the increase in Fluo-deltorphin internalization was caused by
increased receptor availability. Prolonged morphine exposure had no
effect on OR protein levels, as assessed by immunocytochemistry and
Western blotting, suggesting that the increase in bioavailable
ORs was caused by recruitment of reserve receptors from
intracellular stores and not from receptor neosynthesis. Complementary
in vivo studies demonstrated that chronic treatment of
adult rats with morphine (5-15 mg/kg, s.c., every 12 hr)
similarly augmented targeting of ORs to neuronal plasma membranes in
the dorsal horn of the spinal cord. Furthermore, this treatment
markedly potentiated intrathecal
D-[Ala2]deltorphin II-induced
antinociception. Taken together, these results demonstrate that
prolonged stimulation of neurons with morphine markedly increases
recruitment of intracellular ORs to the cell surface, both in
vitro and in vivo. We propose that this type of
receptor subtype cross-mobilization may widen the transduction
repertoire of G-protein-coupled receptors and offer new therapeutic strategies.
Key words:
opiate; trafficking; narcotic; internalization; analgesia; receptor recruitment
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197598-10$05.00/0
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