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

TLDR

Opiates such as morphine are the primary analgesics for chronic pain, yet their long‑term use is limited by tolerance and dependence, prompting strategies that combine morphine with δ opioid receptor ligands to enhance potency, though the underlying molecular basis remains unclear. This study proposes that physical heterodimerization between μ and δ opioid receptors modulates receptor function as a mechanism to improve morphine efficacy. We demonstrate that μ‑δ receptor complexes exist in live cells and native membranes, and that δ‑receptor antagonists increase μ‑opioid receptor binding and signaling activity. δ‑receptor antagonists enhance morphine‑mediated intrathecal analgesia, indicating that μ‑δ heterodimerization can serve as a model for developing novel combination therapies for chronic pain.

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.