PMID- 18022146
OWN - NLM
STAT- MEDLINE
DCOM- 20080317
LR  - 20211020
IS  - 0006-8993 (Print)
IS  - 1872-6240 (Electronic)
IS  - 0006-8993 (Linking)
VI  - 1187
DP  - 2008 Jan 2
TI  - mGluR5 antagonists that block calcium mobilization in vitro also reverse 
      (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo.
PG  - 58-66
AB  - 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.
FAU - Gabra, Bichoy H
AU  - Gabra BH
AD  - Department of Pharmacology and Toxicology, Virginia Commonwealth University 
      Medical Center, P.O. Box 980613, Richmond, VA 23298, USA.
FAU - Smith, Forrest L
AU  - Smith FL
FAU - Navarro, Hernan A
AU  - Navarro HA
FAU - Carroll, F Ivy
AU  - Carroll FI
FAU - Dewey, William L
AU  - Dewey WL
LA  - eng
GR  - R01 DA001647/DA/NIDA NIH HHS/United States
GR  - R01 DA005477/DA/NIDA NIH HHS/United States
GR  - F31 DA016472/DA/NIDA NIH HHS/United States
GR  - DA-020836/DA/NIDA NIH HHS/United States
GR  - DA05477/DA/NIDA NIH HHS/United States
GR  - DA-01647/DA/NIDA NIH HHS/United States
GR  - R37 DA005477/DA/NIDA NIH HHS/United States
GR  - R01 DA020836/DA/NIDA NIH HHS/United States
GR  - K05 DA000480/DA/NIDA NIH HHS/United States
GR  - DA016472/DA/NIDA NIH HHS/United States
GR  - K05-DA00480/DA/NIDA NIH HHS/United States
PT  - Comparative Study
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20071012
PL  - Netherlands
TA  - Brain Res
JT  - Brain research
JID - 0045503
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Grm5 protein, mouse)
RN  - 0 (Pyridines)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (Resorcinols)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 5YR2N37E6D (3,5-dihydroxyphenylglycine)
RN  - 76I7G6D29C (Morphine)
RN  - 7VC0YVI27Y (6-methyl-2-(phenylethynyl)pyridine)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Analgesics, Opioid/agonists
MH  - Animals
MH  - Calcium Signaling/*drug effects/physiology
MH  - Central Nervous System/drug effects/metabolism/physiopathology
MH  - Dose-Response Relationship, Drug
MH  - Drug Tolerance/*physiology
MH  - Excitatory Amino Acid Agonists/pharmacology
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Glutamic Acid/metabolism
MH  - Glycine/analogs & derivatives/pharmacology
MH  - Hyperalgesia/chemically induced/*drug therapy/metabolism
MH  - Male
MH  - Mice
MH  - Morphine/*agonists
MH  - Nociceptors/drug effects/metabolism
MH  - Pain/chemically induced/drug therapy/metabolism
MH  - Placebo Effect
MH  - Pyridines/chemistry/pharmacology
MH  - Receptor, Metabotropic Glutamate 5
MH  - Receptors, Metabotropic Glutamate/*antagonists & inhibitors/metabolism
MH  - Resorcinols/pharmacology
MH  - Synaptic Transmission/drug effects/physiology
PMC - PMC3730269
MID - NIHMS36283
EDAT- 2007/11/21 09:00
MHDA- 2008/03/18 09:00
PMCR- 2013/08/01
CRDT- 2007/11/21 09:00
PHST- 2007/07/16 00:00 [received]
PHST- 2007/09/22 00:00 [revised]
PHST- 2007/10/01 00:00 [accepted]
PHST- 2007/11/21 09:00 [pubmed]
PHST- 2008/03/18 09:00 [medline]
PHST- 2007/11/21 09:00 [entrez]
PHST- 2013/08/01 00:00 [pmc-release]
AID - S0006-8993(07)02382-7 [pii]
AID - 10.1016/j.brainres.2007.10.007 [doi]
PST - ppublish
SO  - Brain Res. 2008 Jan 2;1187:58-66. doi: 10.1016/j.brainres.2007.10.007. Epub 2007 
      Oct 12.