Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson's disease: a behavioral and neurochemical study in reserpinized mice.
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.
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Mattia
M
Volta
Omar S
OS
Mabrouk
Simone
S
Bido
Matteo
M
Marti
Michele
M
Morari
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018846:Excitatory Amino Acids / Q000819:agonists* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D018847:Opioid Peptides / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D012110:Reserpine / Q000633:toxicity*; D000097629:Nociceptin
D001562:Benzimidazoles; D018846:Excitatory Amino Acids; D018847:Opioid Peptides; D010880:Piperidines; D012110:Reserpine; D000097629:Nociceptin; C402921:J 113397