MMG22: A Novel Bivalent Ligand for the Treatment of Neuropathic Pain

Abstract

Functional interactions between the mu opioid receptor (MOR) and the metabotropic glutamate receptor 5 (mGluR5) in pain and analgesia have been well established. MMG22 is a bivalent ligand containing MOR agonist (oxymorphamine) and mGluR5 antagonist (MPEP) pharmacophores tethered by a 22-atom linker. MMG22 has been shown to produce potent analgesia in several models of chronic inflammatory and neuropathic pain. This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of neuropathic pain in mice, as well as its side effect profile and abuse potential. MMG22 reduced mechanical hyperalgesia and spontaneous ongoing pain after SNI, with greater potency early (10 days) as compared to late (30 days) after injury. Systemic administration of MMG22 did not induce place preference in naïve animals, suggesting absence of abuse liability when compared to traditional opioids. MMG22 also lacked the central locomotor, respiratory, and anxiolytic side effects of its monomeric pharmacophores. Evaluation of mRNA expression showed the transcripts for both receptors were co-localized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Teased nerve fiber recordings from the sural nerve of SNI mice show that MMG22 reduces the firing rate of C and Aδ fiber nociceptors evoked by suprathreshold stimuli. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of neuropathic pain by decreasing nociceptor activity without the typical centrally mediated side effects associated with traditional opioids.