Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson's disease: a behavioral and neurochemical study in reserpinized mice

J Neurochem. 2010 Dec;115(6):1543-55. doi: 10.1111/j.1471-4159.2010.07061.x. Epub 2010 Nov 11.

Abstract

The contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced Parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response because N/OFQ peptide (NOP) receptor knockout (NOP(-/-) ) mice were less susceptible to the hypokinetic action of reserpine than wild-type (NOP(+/+) ) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP(-/-) mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP(+/+) mice, being ineffective in NOP(-/-) mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced Parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acids / agonists*
  • Excitatory Amino Acids / physiology
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology*
  • Opioid Peptides / antagonists & inhibitors
  • Opioid Peptides / deficiency
  • Opioid Peptides / physiology*
  • Parkinsonian Disorders / chemically induced*
  • Parkinsonian Disorders / physiopathology*
  • Piperidines / pharmacology
  • Reserpine / toxicity*

Substances

  • Benzimidazoles
  • Excitatory Amino Acids
  • J 113397
  • Opioid Peptides
  • Piperidines
  • nociceptin
  • Reserpine