Analgesic activity of metabotropic glutamate receptor 1 antagonists on spontaneous post-operative pain in rats.

Abstract

Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu1 receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED50s of 10, 50, 50, and 65 micromol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu1 receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu1 receptor antagonists as novel analgesics.

• Authors: Chang Z Zhu, Scott Baker, Odile EI-Kouhen, Sonya G Lehto, Peter R Hollingsworth, Donna M Gauvin, Gricelda Hernandez, GuoZhu Zheng, Renjie Chang, Robert B Moreland, Andrew O Stewart, Jorge D Brioni, Prisca Honore
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 580 Issue 3 Pg. 314-21 (Feb 12 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18054908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 9-dimethylamino-3-(4-ethylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one
• 9-dimethylamino-3-(4-methylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one
• 9-dimethylamino-3-cycloheptyl-3H-5-thia-1,3,6-triazafluoren-4-one
• A-841720
• Analgesics, Non-Narcotic
• Dimethylamines
• Excitatory Amino Acid Antagonists
• Heterocyclic Compounds, 3-Ring
• Pyridines
• Pyrimidinones
• Receptors, Metabotropic Glutamate
• Resorcinols
• Thiophenes
• Tritium
• 3,5-dihydroxyphenylglycine
• Morphine
• 6-methyl-2-(phenylethynyl)pyridine
• Calcium
• Glycine

Topics

• Analgesics, Non-Narcotic (chemistry, pharmacology)
• Animals
• Calcium (metabolism)
• Cell Membrane (drug effects, metabolism)
• Cerebellum (cytology, drug effects, metabolism)
• Dimethylamines (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (chemistry, pharmacology)
• Exploratory Behavior (drug effects)
• Fluorometry (methods)
• Glycine (analogs & derivatives, pharmacology)
• Heterocyclic Compounds, 3-Ring (chemistry, pharmacology)
• Hindlimb (surgery)
• Male
• Molecular Structure
• Morphine (pharmacology)
• Pain, Postoperative (etiology, prevention & control)
• Pyridines (chemistry, pharmacology)
• Pyrimidinones (chemistry, pharmacology)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (antagonists & inhibitors)
• Resorcinols (pharmacology)
• Rotarod Performance Test (methods)
• Thiophenes (chemistry, pharmacology)
• Tritium