A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesia

doi:10.1073/pnas.0307601101

A role for heterodimerization of μ and δ opiate receptors in enhancing morphine analgesia

^†Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; ^*Department of Pharmacology, New York University School of Medicine, New York, NY 10016; ^‡Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021; and ^§Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 17, 2004 (received for review November 17, 2003)

Abstract

Opiates such as morphine are the choice analgesic in the treatment of chronic pain. However their long-term use is limited because of the development of tolerance and dependence. Due to its importance in therapy, different strategies have been considered for making opiates such as morphine more effective, while curbing its liability to be abused. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, δ opioid receptor ligands have been useful in enhancing morphine's potency. The underlying molecular basis for these observations is not understood. We propose the modulation of receptor function by physical association between μ and δ opioid receptors as a potential mechanism. In support of this hypothesis, we show that μ-δ interacting complexes exist in live cells and native membranes and that the occupancy of δ receptors (by antagonists) is sufficient to enhance μ opioid receptor binding and signaling activity. Furthermore, δ receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between μ-δ opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: lakshmi.devi{at}mssm.edu.
Abbreviations: GPCR, G protein-coupled receptor; BRET, bioluminescence resonance energy transfer; CHO, Chinese hamster ovary; DAMGO, [d-Ala²,N-MePhe⁴,Gly⁵-ol]enkephalin; YFP, yellow fluorescent protein; Delt, deltorphin; Luc, luciferase; TIPPψ, Tyr-Ticψ-(CH2NH)Phe-Phe.
This paper was submitted directly (Track II) to the PNAS office.