Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception

The low effectiveness of morphine and related mu opioid analgesics for the treatment of chronic inflammatory pain is a result of opioid-induced release of proinflammatory cytokines and glutamate that lower the pain threshold. In this regard, the use of opioids with metabotropic glutamate-5 receptor (mGluR ₅) antagonist has been reported to increase the efficacy of morphine and prevent the establishment of adverse effects during chronic use. Given the presence of opioid receptors (MORs) and mGluR₅ in glia and neurons, together with reports that suggest coexpressed MOR/mGluR₅ receptors in cultured cells associate as a heteromer, the possibility that such a heteromer could be a target in vivo was addressed by the design and synthesis of a series of bivalent ligands that contain mu opioid agonist and mGluR ₅ antagonist pharmacophores linked through spacers of varying length (10-24 atoms). The series was evaluated for antinociception using the tail-flick and von Frey assays in mice pretreated with lipopolysaccharide (LPS) or in mice with bone cancer. In LPS-pretreated mice, MMG22 (4c, 22-atom spacer) was the most potent member of the series (intrathecal ED₅₀ ∼9 fmol per mouse), whereas in untreated mice its ED₅₀ was more than three orders of magnitude higher. As members of the series with shorter or longer spacers have ≥500-fold higher ED_50s in LPS-treated mice, the exceptional potency of MMG22 may be a result of the optimal bridging of protomers in a putative MOR-mGluR5 heteromer. The finding that MMG22 possesses a >10 ⁶ therapeutic ratio suggests that it may be an excellent candidate for treatment of chronic, intractable pain via spinal administration.