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Functional Interactions between µ Opioid and _2A-Adrenergic Receptors

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York

Adrenergic and opioid receptors belong to the rhodopsin family of G-protein coupled receptors, couple to analogous signal transduction pathways, and affect the nociceptive system. Although a number of previous studies have reported functional interactions between these two receptors, the basis for this has not been well explored. We propose that direct receptor-receptor interactions could account, in part, for opioid-adrenergic cross-talk. In this report, we have addressed this using biophysical, biochemical, and pharmacological studies. We show that µ opioid and _2A adrenergic receptors reside in close proximity in live cells using the bioluminescence resonance energy transfer assay. These receptors colocalize to proximal dendrites in primary hippocampal neurons. µ-_2A Receptor complexes can be isolated from heterologous cells or primary neurons coexpressing these receptors. In these cells, the activation of either µ or _2A receptor leads to a significant increase in the level of immunoprecipitable µ-_2A complexes, whereas activation of both receptors leads to a significant decrease. The implications of these effects on signaling were examined using the agonist-mediated increase in G-protein activity and mitogen-activated protein kinase activity. We find that activation of either µ or _2A receptors leads to an increase in the extent of signaling, whereas activation of both receptors leads to a decrease. The increase in signaling by individual ligands and decrease by a combination of ligands is also seen in primary spinal cord neurons endogenously expressing these receptors. Taken together, these results suggest that physical associations between µ and _2A receptors could play a role in the functional interactions between these receptors.

Received May 19, 2003; accepted September 3, 2003.

Address correspondence to: Lakshmi A. Devi, Ph.D., Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, 19-84 Annenberg Building, One Gustave L. Levy Place, New York, NY 10029. E-mail: lakshmi.devi{at}mssm.edu

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