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 |
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Authors: | El-Kouhen O Lehto S G Pan J B Chang R Baker S J Zhong C Hollingsworth P R Mikusa J P Cronin E A Chu K L McGaraughty S P Uchic M E Miller L N Rodell N M Patel M Bhatia P Mezler M Kolasa T Zheng G Z Fox G B Stewart A O Decker M W Moreland R B Brioni J D Honore P |
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Institution: | Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA. |
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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. |
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Keywords: | metabotropic glutamate receptor pain cognitive function |
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