MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores connected by a 22-atom linker. Intrathecal (i.t.) administration of MMG22 to inflamed mice has been reported to produce fmol-range antinociception in the reversal of LPS-induced hyperalgesia. MMG22 reduced hyperalgesia in the spared nerve injury (SNI) model of neuropathic pain at 10 days after injury but not at 30 days after injury, perhaps related to the inflammation that occurs early after injury but subsequently subsides. The present study determined the efficacy of MMG22 in cisplatin-treated male mice in order to provide data relating to the efficacy of MMG22 in the treatment of neuropathic pain that is associated with inflammation. Groups of eight mice each received daily intraperitoneal (i.p.) injections of cisplatin for seven days to produce robust mechanical allodynia defined by the decrease in withdrawal threshold using an electronic von Frey applied to the plantar surface of the hind paw. Intrathecal administration of MMG22 potently reduced mechanical hyperalgesia (ED50 0.04 fmol/mouse) without tolerance, whereas MMG10 was essentially inactive. Morphine was less potent than MMG22 by >5-orders of magnitude and displayed tolerance. Subcutaneous MMG22 was effective (ED50 = 2.41 mg/kg) and devoid of chronic tolerance. We propose that MMG22 induces the formation of a MOR-mGluR5 heteromer through selective interaction with the upregulated NR2B subunit of activated NMDAR, in view of the 4600-fold reduction of i.t. MMG22 antinociception by the selective NR2B antagonist, Ro25-6981. A possible explanation for the substantially reduced potency for MMG22 in the SNI model is discussed.
|Original language||English (US)|
|Number of pages||8|
|State||Published - Apr 15 2023|
Bibliographical noteFunding Information:
This work was supported by NIH grant CA241627.
We thank Dr. Sergey Khasabov for help in preparing the figures. This work was supported by NIH grants CA241627 and HL135895 (DAS). We thank the Dept. of Medicinal Chemistry and the College of Pharmacy, University of Minnesota, for also supporting this study.
© 2023 IBRO
- neuropathic pain
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural