Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist.
OBJECTIVE
To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain.


METHODS
We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function.


RESULTS
At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7+/-3.9 and 1.0 +/- 0.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50 = 23 micromol kg(-1)) and monoiodoacetate-induced joint pain (ED50 = 43 micromol kg(-1)). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50 = 28 and 27 micromol kg(-1), respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests.


CONCLUSIONS
The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.
El-Kouhen
O
O
Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
Lehto
S G
SG
Pan
J B
JB
Chang
R
R
Baker
S J
SJ
Zhong
C
C
Hollingsworth
P R
PR
Mikusa
J P
JP
Cronin
E A
EA
Chu
K L
KL
McGaraughty
S P
SP
Uchic
M E
ME
Miller
L N
LN
Rodell
N M
NM
Patel
M
M
Bhatia
P
P
Mezler
M
M
Kolasa
T
T
Zheng
G Z
GZ
Fox
G B
GB
Stewart
A O
AO
Decker
M W
MW
Moreland
R B
RB
Brioni
J D
JD
Honore
P
P
D000698:Analgesia; D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005453:Fluorescence; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
C516995:A-841720; D018691:Excitatory Amino Acid Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1