The Mu-Delta Opioid Receptor Heterodimer May Evoke Similar Signaling Within The Striatum, Periadqueductal Gray, And Brainstem

Opioid drugs like morphine are the gold standard for treating acute and chronic pain, but they induce detrimental side effects such as tolerance and dependence. It has been suggested that the mu-delta opioid receptor heterodimer (MDOR) enhances some of these side effects and that heterodimer targeted drugs could be a solution to weaken these side effects. We have thus created an MDOR selective antagonist called D24M with a ~100-fold in vitro selectivity for the MDOR over the monomers. We then used D24M to examine MDOR physiology in mice. We found that intracerebroventricular (icv) injection of 1 nmol D24M strongly increased oxymorphone anti-nociception in models of tail flick, paw incision, and chemotherapy-induced neuropathic pain, but had no effects on morphine or buprenorphine anti-nociception. D24M also strongly decreased morphine withdrawal in acute and chronic dependence models. We then tested ERK activation via western blot analysis with the injection of D24M or vehicle and various opioid drugs. We found that D24M has similar effects on ERK pathway activation for each part of the three tested brain regions (striatum, periaqueductal grey [PAG], and brainstem); further confirming that ERK is a possible pathway for the MDOR to promote kinase activation. This discovery could be a stepping stone for determining the signaling mechanisms of the MDOR