Analgesic activity of metabotropic glutamate receptor 1 antagonists on spontaneous post-operative pain in rats.
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.
Zhu
Chang Z
CZ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. Chang.Z.Zhu@abbott.com
Baker
Scott
S
EI-Kouhen
Odile
O
Lehto
Sonya G
SG
Hollingsworth
Peter R
PR
Gauvin
Donna M
DM
Hernandez
Gricelda
G
Zheng
GuoZhu
G
Chang
Renjie
R
Moreland
Robert B
RB
Stewart
Andrew O
AO
Brioni
Jorge D
JD
Honore
Prisca
P
D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004123:Dimethylamines / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005470:Fluorometry / Q000379:methods; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006614:Hindlimb / Q000601:surgery; D008297:Male; D015394:Molecular Structure; D009020:Morphine / Q000494:pharmacology; D010149:Postoperative Pain / Q000209:etiology / Q000517:prevention & control*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000494:pharmacology; D045442:Rotarod Performance Test / Q000379:methods; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D014316:Tritium
C507031:9-dimethylamino-3-(4-ethylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one; C529171:9-dimethylamino-3-(4-methylphenyl)-3H-5-thia-1,3,6-triazafluoren-4-one; C529170:9-dimethylamino-3-cycloheptyl-3H-5-thia-1,3,6-triazafluoren-4-one; C516995:A-841720; D018712:Analgesics, Non-Narcotic; D004123:Dimethylamines; D018691:Excitatory Amino Acid Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D011725:Pyridines; D011744:Pyrimidinones; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D013876:Thiophenes; D014316:Tritium; C079215:3,5-dihydroxyphenylglycine; D009020:Morphine; C121465:6-methyl-2-(phenylethynyl)pyridine; D002118:Calcium; D005998:Glycine