title: Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine tolerance in mice.
abstract: Intracerebroventricular (i.c.v.) injection of phospholipase C inhibitors and structurally dissimilar PKC inhibitors were shown to completely reverse morphine antinociceptive tolerance in mice. Since Group I metabotropic glutamate receptors (mGlu(1) and mGlu(5)) activate phospholipase C through Galpha(q) Galpha(11) proteins, we hypothesized that morphine tolerance could occur through an increase in mGlu(1) and mGlu(5) receptor stimulation. Seventy-two hours after implantation of placebo or 75 mg morphine pellets, mice were tested in the 56 degrees C warm-water tail-withdrawal test following i.c.v. injection of vehicle or test drug. The mGlu(1) receptor antagonist CPCCOEt (7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester) partly but significantly reversed morphine tolerance. The mGlu(5) receptor antagonist MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride) also partly reversed the antinociceptive tolerance. Co-administering CPCCOEt with MPEP completely reversed the tolerance. Furthermore, the mixed mGlu(1)/mGlu(5) antagonist AIDA ((RS)-1-Aminoindan-1,5-dicarboxylic acid) also completely reversed the tolerance. Thus, greater mGlu(1) and mGlu(5) receptor stimulation during morphine tolerance may lead to persistent activation of the phosphatidylinositol cascade.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, P.O. Box 980613, Richmond, VA 23298-0613, USA. flsmith1@vcu.edu
authors.forename: Forrest L
authors.initials: FL
authors.lastname: Smith
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Ruby R
authors.initials: RR
authors.lastname: Javed
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004361:Drug Tolerance; D007189:Indans / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013623:Tail
chemical_list: C095756:1-aminoindan-1,5-dicarboxylic acid; D000701:Analgesics, Opioid; D007189:Indans; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D009020:Morphine; C121465:6-methyl-2-(phenylethynyl)pyridine