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.

Abstract

BACKGROUND AND PURPOSE:

To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

• 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: British journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 6 Pg. 761-74 (Nov 2006) ISSN: 0007-1188 [Print] England
• PMID: 17016515 (Publication Type: Journal Article)

Chemical References

• A-841720
• Excitatory Amino Acid Antagonists
• Heterocyclic Compounds, 3-Ring
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor type 1

Topics

• Analgesia
• Animals
• Cells, Cultured
• Cognition (drug effects)
• Excitatory Amino Acid Antagonists (pharmacology)
• Fluorescence
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Male
• Motor Activity (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptors, Metabotropic Glutamate (antagonists & inhibitors)