The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.
BACKGROUND
Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders.


OBJECTIVE
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.


CONCLUSIONS
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.
Varty
Geoffrey B
GB
Department of Neurobiology, Schering Plough Research Institute, Kenilworth, NJ 07033, USA. Geoffrey.Varty@SPCorp.com.
Grilli
Mariagrazia
M
Forlani
Angelo
A
Fredduzzi
Silva
S
Grzelak
Michael E
ME
Guthrie
Donald H
DH
Hodgson
Robert A
RA
Lu
Sherry X
SX
Nicolussi
Elisa
E
Pond
Annamarie J
AJ
Parker
Eric M
EM
Hunter
John C
JC
Higgins
Guy A
GA
Reggiani
Angelo
A
Bertorelli
Rosalia
R
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity; D011799:Quinazolines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity
C504780:(4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl; C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000700:Analgesics; D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D011725:Pyridines; D011799:Quinazolines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; C121465:6-methyl-2-(phenylethynyl)pyridine