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Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice
Author(s) -
Volta Mattia,
Mabrouk Omar S.,
Bido Simone,
Marti Matteo,
Morari Michele
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.07061.x
Subject(s) - nop , nociceptin receptor , reserpine , glutamate receptor , chemistry , medicine , endocrinology , neurochemical , pharmacology , receptor , opioid peptide , opioid
J. Neurochem. (2010) 115, 1543–1555. 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.