The bivalent ligand, MMG22, reduces neuropathic pain after nerve injury without the side effects of traditional opioids

Rebecca H Speltz Paiz, Mary M Lunzer, Sarah S. Shueb, Eyup Akgün, Rachelle Reed, Alex Kalyuzhny, Philip S. Portoghese, Donald A. Simone

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 (NP). This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of NP 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 naive 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 colocalized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of NP without the typical centrally mediated side effects associated with traditional opioids.

Original languageEnglish (US)
Pages (from-to)2041-2057
Number of pages17
Issue number9
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
The authors thank Dr George Wilcox for reading an earlier version of the manuscript. This work was supported by NIH grants HL135895 and CA241627 (D.A.S.), and DA030316 (P.S.P.). R. Speltz was supported by MSTP NIGMS 5T32GM008244 and National Institute on Drug Abuse Grant 5T32DA007234.

Publisher Copyright:
© 2020 International Association for the Study of Pain.


  • Antihyperalgesia
  • Mu opiate receptor
  • Spared nerve injury
  • mGluR5


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