a-794282 and Pain--Postoperative

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.

Topics: Analgesics, Non-Narcotic; Animals; Calcium; Cell Membrane; Cerebellum; Dimethylamines; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fluorometry; Glycine; Heterocyclic Compounds, 3-Ring; Hindlimb; Male; Molecular Structure; Morphine; Pain, Postoperative; Pyridines; Pyrimidinones; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Resorcinols; Rotarod Performance Test; Thiophenes; Tritium