RATIONALE: Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders. OBJECTIVES: This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety. METHODS: The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects. RESULTS: The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg. CONCLUSION: Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.
RATIONALE: Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders. OBJECTIVES: This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety. METHODS: The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouseformalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects. RESULTS: The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg. CONCLUSION: Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.
Authors: F Gasparini; K Lingenhöhl; N Stoehr; P J Flor; M Heinrich; I Vranesic; M Biollaz; H Allgeier; R Heckendorn; S Urwyler; M A Varney; E C Johnson; S D Hess; S P Rao; A I Sacaan; E M Santori; G Veliçelebi; R Kuhn Journal: Neuropharmacology Date: 1999-10 Impact factor: 5.250
Authors: Gene G Kinney; Maryann Burno; Una C Campbell; Lisa M Hernandez; Dana Rodriguez; Linda J Bristow; P Jeffrey Conn Journal: J Pharmacol Exp Ther Date: 2003-03-26 Impact factor: 4.030
Authors: Aleksandra Klodzinska; Ewa Tatarczyńska; Ewa Chojnacka-Wójcik; Gabriel Nowak; Nicholas D P Cosford; Andrzej Pilc Journal: Neuropharmacology Date: 2004-09 Impact factor: 5.250
Authors: A Pilc; A Kłodzińska; P Brański; G Nowak; A Pałucha; B Szewczyk; E Tatarczyńska; E Chojnacka-Wójcik; J M Wierońska Journal: Neuropharmacology Date: 2002-08 Impact factor: 5.250
Authors: Sophie E Holmes; Matthew J Girgenti; Margaret T Davis; Robert H Pietrzak; Nicole DellaGioia; Nabeel Nabulsi; David Matuskey; Steven Southwick; Ronald S Duman; Richard E Carson; John H Krystal; Irina Esterlis Journal: Proc Natl Acad Sci U S A Date: 2017-07-17 Impact factor: 11.205
Authors: Clyde W Hodge; Michael F Miles; Amanda C Sharko; Rebekah A Stevenson; Jennie R Hillmann; Veronique Lepoutre; Joyce Besheer; Jason P Schroeder Journal: Psychopharmacology (Berl) Date: 2005-11-15 Impact factor: 4.530
Authors: O El-Kouhen; S G Lehto; J B Pan; R Chang; S J Baker; C Zhong; P R Hollingsworth; J P Mikusa; E A Cronin; K L Chu; S P McGaraughty; M E Uchic; L N Miller; N M Rodell; M Patel; P Bhatia; M Mezler; T Kolasa; G Z Zheng; G B Fox; A O Stewart; M W Decker; R B Moreland; J D Brioni; P Honore Journal: Br J Pharmacol Date: 2006-10-03 Impact factor: 8.739
Authors: Hyekyung P Cho; Darren W Engers; Daryl F Venable; Colleen M Niswender; Craig W Lindsley; P Jeffrey Conn; Kyle A Emmitte; Alice L Rodriguez Journal: ACS Chem Neurosci Date: 2014-05-15 Impact factor: 4.418
Authors: Michael C Montana; Laura F Cavallone; Kristi K Stubbert; Andrei D Stefanescu; Evan D Kharasch; Robert W Gereau Journal: J Pharmacol Exp Ther Date: 2009-06-10 Impact factor: 4.030