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The Journal of Neuroscience, 0000, 20:RC110:1-5
RAPID COMMUNICATION
Heterodimerization of µ and  Opioid Receptors: A Role in
Opiate Synergy
I.
Gomes,
B. A.
Jordan,
A.
Gupta,
N.
Trapaidze,
V.
Nagy, and
L. A.
Devi
Departments of Pharmacology and Anesthesiology, New York University
School of Medicine, New York, New York 10016
Opiate analgesics are widely used in the treatment of severe pain.
Because of their importance in therapy, different strategies have been
considered for making opiates more effective while curbing their
liability to be abused. Although most opiates exert their analgesic
effects primarily via µ opioid receptors, a number of studies have
shown that  receptor-selective drugs can enhance their potency. The
molecular basis for these findings has not been elucidated previously.
In the present study, we examined whether heterodimerization of µ and
receptors could account for the cross-modulation previously
observed between these two receptors. We find that co-expression of µ and receptors in heterologous cells followed by selective
immunoprecipitation results in the isolation of µ- heterodimers.
Treatment of these cells with extremely low doses of certain
-selective ligands results in a significant increase in the binding
of a µ receptor agonist. Similarly, treatment with µ-selective
ligands results in a significant increase in the binding of a receptor agonist. This robust increase is also seen in SKNSH
cells that endogenously express both µ and receptors.
Furthermore, we find that a receptor antagonist enhances both the
potency and efficacy of the µ receptor signaling; likewise a µ antagonist enhances the potency and efficacy of the receptor
signaling. A combination of agonists (µ and receptor selective)
also synergistically binds and potentiates signaling by activating the
µ- heterodimer. Taken together, these studies show that
heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have important clinical ramifications and may provide new foundations for more effective therapies.
Key words:
receptor subtypes; agonist; antagonist; enkephalin; Deltorphin II; DAMGO; DPDPE; TIPP ; G-protein-coupled receptor; oligomerization; MAP kinase
Copyright © 0000 Society for Neuroscience 0270-6474/00/$05.00/0
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|
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