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.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Pain, Postoperative/prevention & control , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Analgesics, Non-Narcotic/chemistry , Animals , Calcium/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Cerebellum/cytology , Cerebellum/drug effects , Cerebellum/metabolism , Dimethylamines/chemistry , Dimethylamines/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/chemistry , Exploratory Behavior/drug effects , Fluorometry/methods , Glycine/analogs & derivatives , Glycine/pharmacology , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Hindlimb/surgery , Male , Molecular Structure , Morphine/pharmacology , Pain, Postoperative/etiology , Pyridines/chemistry , Pyridines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Resorcinols/pharmacology , Rotarod Performance Test/methods , Thiophenes/chemistry , Thiophenes/pharmacology , TritiumABSTRACT
Metabotropic glutamate receptors (mGluRs) have previously been shown to play a role in pain transmission during inflammatory or neuropathic pain states. However, the role of mGluR5 in post-operative pain remains to be fully investigated. The present study was conducted to characterize analgesic activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in the skin-incision-induced post-operative pain model in rats. MPEP is a potent and selective mGluR5 antagonist with high affinity (K(i)=6.3+/-0.9 nM) in rat cortex using [(3)H]-MPEP as a radioligand, while not competing with the mGluR1-selective radioligand [(3)H]-R214127 (K(i)>10,000 nM) in rat cerebellum. Post-operative pain was examined 2 h following surgery using weight-bearing (WB) difference between injured and uninjured paws as a measure of non-evoked pain. In this model, MPEP, as morphine, showed dose-dependent effects and full efficacy after systemic administration (ED(50)=15 mg/kg, i.p. for MPEP, ED(50)=1.3 mg/kg, s.c. for morphine). In addition, intrathecal (i.t.) and intracerebroventricular (i.c.v.) MPEP reduced WB difference (ED(50)=65 microg/rat i.t. and ED(50)=200 microg/rat i.c.v.). Interestingly, intraplantar (i.pl.) injection of MPEP either before or after surgery induced a similar reduction in WB difference (ED(50)=90 microg/rat, i.pl.) while contralateral i.pl. MPEP injection did not produce any effect. These results demonstrate that both peripheral and central mGluR5 receptors play a role in nociceptive transmission observed during post-operative pain. In addition, the data suggest that mGluR5 antagonists could offer a new therapeutic approach to the treatment of post-operative pain.
