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

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, delta 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 mu and delta opioid receptors as a potential mechanism. In support of this hypothesis, we show that mu-delta interacting complexes exist in live cells and native membranes and that the occupancy of delta receptors (by antagonists) is sufficient to enhance mu opioid receptor binding and signaling activity. Furthermore, delta receptor antagonists enhance morphine-mediated intrathecal analgesia. Thus, heterodimeric associations between mu-delta opioid receptors can be used as a model for the development of novel combination therapies for the treatment of chronic pain and other pathologies.