title: mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo.
abstract: The present study comparatively evaluated the potency of a series of new phenylethyl[1,2,4]methyltriazines which are analogues of the classical metabotropic glutamate (mGlu) receptor subtype 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in blocking hyperalgesia induced by the group I mGlu receptor agonist (S)-3,5-DHPG as well as in reversing morphine antinociceptive tolerance in mice. Hyperalgesia was assessed in mice using the tail immersion test. Intrathecal (i.t.) pre-treatment with the test compounds 5-methyl-3-phenylethynyl-[1,2,4]triazine (RTI-4229-707), 5-methyl-3-(4-phenoxy-phenylethynyl-[1,2,4]triazine (RTI-4229-766), and 3-(3-methylphenylethynyl)-5-methyl-[1,2,4]triazine (RTI-4229-787) resulted in a dose-dependent blockade of (S)-3,5-DHPG-induced hyperalgesia. The inhibitory dose-50 (ID(50)) values were 0.49, 0.72 and 0.44 nmol/mouse, for RTI-4229-707, RTI-4229-766 and RTI-4229-787, respectively, compared to 18.63 nmol/mouse for MPEP. The other two compounds tested 3-(2,5-dimethylphenylethynyl)-5-methyl[1,2,4]triazine (RTI-4229-785) and 3-(2-methylphenylethynyl)-5-methyl[1,2,4]triazine (RTI-4229-828) were totally inactive. Morphine tolerance was induced in mice by implanting a 75 mg morphine pellet and assessing morphine-induced antinociception 72-h later. The morphine-pelleted mice showed a 5.5-fold tolerance to the antinociceptive effect of acute morphine compared to placebo-pelleted mice in the tail immersion test. Intracerebroventricular (i.c.v.) administration of the three active mGluR5 antagonists dose-dependently reversed morphine antinociceptive tolerance. The ID(50) values were 57.7, 25.8 and 64.3 nmol/mouse, for RTI-4229-707, RTI-4229-766 and RTI-4229-787, respectively, compared to 1050 nmol/mouse for MPEP. Similar to the hyperalgesia study, test compounds RTI-4229-785 and RTI-4229-828 were totally inactive in reversing morphine tolerance. These results are in agreement with our previous study in which we demonstrated that the same active mGluR5 antagonists blocked glutamate-mediated mobilization of internal calcium in a selective mGluR5 in vitro efficacy assay.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, P.O. Box 980613, Richmond, VA 23298, USA.
authors.forename: Bichoy H
authors.initials: BH
authors.lastname: Gabra
authors.forename: Forrest L
authors.initials: FL
authors.lastname: Smith
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
mesh_terms: D000701:Analgesics, Opioid / Q000819:agonists; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000819:agonists*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D015990:Placebo Effect; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D018698:Glutamic Acid; C079215:3,5-dihydroxyphenylglycine; D009020:Morphine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine