title: Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model.
abstract: The therapeutic management of chronic pain associated with many cancers is problematic due to the development of tolerance and other adverse effects during the disease progression. Recently we reported on a bivalent ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3-21 days that correlated with the progressive increase in hyperalgesia induced by bone tumor growth following implantation of fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the cancer is possibly due to inhibition of NMDA receptor-mediated hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing tumor-induced nociception. In view of the high potency, long duration (>24h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than morphine and other opiates in the treatment of chronic cancer pain and to serve as a novel pharmacologic tool.
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.
authors.forename: Branden A
authors.initials: BA
authors.lastname: Smeester
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Eyup
authors.initials: E
authors.lastname: Akgün
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, United States.
authors.forename: Alvin J
authors.initials: AJ
authors.lastname: Beitz
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States. Electronic address: porto001@umn.edu.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications* / Q000378:metabolism; D045744:Cell Line, Tumor; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009020:Morphine / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D000700:Analgesics; C578936:Grm5 protein, mouse; D008024:Ligands; D064529:Receptor, Metabotropic Glutamate 5; D017450:Receptors, Opioid, mu; D009020:Morphine
keywords: MPEP: CID:3025961; Morphine: CID:5288826