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

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.

• Authors: Mattia Volta, Omar S Mabrouk, Simone Bido, Matteo Marti, Michele Morari
• Journal: Journal of neurochemistry (J Neurochem) Vol. 115 Issue 6 Pg. 1543-55 (Dec 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20950413 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Chemical References

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

Topics

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