Heterodimerization of mu and delta opioid receptors: A role in opiate synergy

Opiate analgesics are widely used in the treatment of severe pain. Because of their importance in therapy, different strategies have been considered f or making opiates more effective while curbing their liability to be abused . Although most opiates exert their analgesic effects primarily via mu opio id receptors, a number of studies have shown that delta 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 mu and delta receptors could account for the cross-mo dulation previously observed between these two receptors. We find that co-e xpression of mu and delta receptors in heterologous cells followed by selec tive immunoprecipitation results in the isolation of mu-delta heterodimers. Treatment of these cells with extremely low doses of certain delta -select ive ligands results in a significant increase in the binding of a mu recept or agonist. Similarly, treatment with mu -selective ligands results in a si gnificant increase in the binding of a delta receptor agonist. This robust increase is also seen in SKNSH cells that endogenously express both mu and delta receptors. Furthermore, we find that a delta receptor antagonist enha nces both the potency and efficacy of the mu receptor signaling; likewise a mu antagonist enhances the potency and efficacy of the d receptor signalin g. A combination of agonists (mu and delta receptor selective) also synergi stically binds and potentiates signaling by activating the mu-delta heterod imer. Taken together, these studies show that heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have importan t clinical ramifications and may provide new foundations for more effective therapies.