Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism

Neurobiol Dis. 2008 Jun;30(3):430-438. doi: 10.1016/j.nbd.2008.02.011. Epub 2008 Mar 8.

Abstract

Endogenous nociceptin/orphanin FQ (N/OFQ) inhibits the activity of dopamine neurons in the substantia nigra and affects motor behavior. In this study we investigated whether a N/OFQ receptor (NOP) antagonist, J-113397, can modify movement in naive mice and nonhuman primates and attenuate motor deficits in MPTP-treated parkinsonian animals. J-113397 facilitated motor activity in naïve mice at low doses (0.1-1 mg/kg) and inhibited it at higher ones (10 mg/kg). Likewise, in MPTP-treated mice, J-113397 reversed motor deficit at 0.01 mg/kg but worsened hypokinesia at higher doses (1 mg/kg). In naïve nonhuman primates, J-113397, ineffective up to 1 mg/kg, produced inconsistent motor improvements at 3 mg/kg. Conversely, in parkinsonian primates J-113397 (0.01 mg/kg) reversed parkinsonism, being most effective against hypokinesia. We conclude that endogenous N/OFQ modulates motor activity in mice and nonhuman primates and contributes to parkinsonian symptoms in MPTP-treated animals. NOP receptor antagonists may represent a novel approach to Parkinson's disease.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • MPTP Poisoning / metabolism*
  • MPTP Poisoning / physiopathology
  • MPTP Poisoning / prevention & control*
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Skills / drug effects
  • Motor Skills / physiology
  • Narcotic Antagonists*
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Receptors, Opioid / physiology*

Substances

  • Benzimidazoles
  • J 113397
  • Narcotic Antagonists
  • Piperidines
  • Receptors, Opioid
  • nociceptin receptor