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Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

Peterson, Cristina D.a; Kitto, Kelley F.b; Akgün, Eyupb,c,d; Lunzer, Mary M.b,c,d; Riedl, Maureen S.b; Vulchanova, Lucyb; Wilcox, George L.b,d,e; Portoghese, Philip S.b,c,d; Fairbanks, Carolyn A.a,b,d,*

doi: 10.1097/j.pain.0000000000001050
Research Paper

The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in the spinal cord. MMG22, a bivalent ligand containing 2 pharmacophores separated by 22 atoms, which simultaneously activates MOR and antagonizes mGluR5, has been shown to produce potent reversal of tactile hypersensitivity in rodent models of lipopolysaccharide (LPS)-and bone cancer–induced chronic pain. This study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Furthermore, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks after spared nerve injury, tactile hypersensitivity was reversed in mice by the intrathecal injection of MMG22 (0.01-10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10- to 14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Coadministration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. This study indicates that in the spared nerve injury–induced model of neuropathic pain, the 2 pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in the potency of MMG22 and MMG10, compared with oxymorphone and MPEP, may reflect the synergistic interaction of the 2 pharmacophores of the bivalent ligand acting at their respective separate receptor monomers.

aGraduate Program in Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

Departments of bNeuroscience,

cMedicinal Chemistry,

dPharmacology and

eDermatology, University of Minnesota, Minneapolis, MN, USA

Corresponding author. Address: University of Minnesota, College of Pharmacy 9-177 Weaver Densford Hall, 308 Harvard St S.E. Minneapolis, MN 55455, USA. Tel.: +1 (612) 625-2945. E-mail address: (C. A. Fairbanks).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received March 27, 2017

Received in revised form August 03, 2017

Accepted August 21, 2017

© 2017 International Association for the Study of Pain
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