Inhibition of inflammatory and neuropathic pain by targeting a Mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR₅)

Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR₅ heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR₅ antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED₅₀ = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ∼3500× more potent than a mixture of mu agonist and CCR₅ antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR₅ heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR₅ heteromer as a novel target for the treatment of chronic pain.