title: 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: 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: O
authors.initials: O
authors.lastname: El-Kouhen
authors.forename: S G
authors.initials: SG
authors.lastname: Lehto
authors.forename: J B
authors.initials: JB
authors.lastname: Pan
authors.forename: R
authors.initials: R
authors.lastname: Chang
authors.forename: S J
authors.initials: SJ
authors.lastname: Baker
authors.forename: C
authors.initials: C
authors.lastname: Zhong
authors.forename: P R
authors.initials: PR
authors.lastname: Hollingsworth
authors.forename: J P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: E A
authors.initials: EA
authors.lastname: Cronin
authors.forename: K L
authors.initials: KL
authors.lastname: Chu
authors.forename: S P
authors.initials: SP
authors.lastname: McGaraughty
authors.forename: M E
authors.initials: ME
authors.lastname: Uchic
authors.forename: L N
authors.initials: LN
authors.lastname: Miller
authors.forename: N M
authors.initials: NM
authors.lastname: Rodell
authors.forename: M
authors.initials: M
authors.lastname: Patel
authors.forename: P
authors.initials: P
authors.lastname: Bhatia
authors.forename: M
authors.initials: M
authors.lastname: Mezler
authors.forename: T
authors.initials: T
authors.lastname: Kolasa
authors.forename: G Z
authors.initials: GZ
authors.lastname: Zheng
authors.forename: G B
authors.initials: GB
authors.lastname: Fox
authors.forename: A O
authors.initials: AO
authors.lastname: Stewart
authors.forename: M W
authors.initials: MW
authors.lastname: Decker
authors.forename: R B
authors.initials: RB
authors.lastname: Moreland
authors.forename: J D
authors.initials: JD
authors.lastname: Brioni
authors.forename: P
authors.initials: P
authors.lastname: Honore
mesh_terms: 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*
chemical_list: C516995:A-841720; D018691:Excitatory Amino Acid Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1