Stimulation of delta opioid receptors located in substantia nigra reticulata but not globus pallidus or striatum restores motor activity in 6-hydroxydopamine lesioned rats: new insights into the role of delta receptors in parkinsonism.
The delta opioid peptide (DOP) receptor has been proposed as a target in the symptomatic therapy of Parkinson's disease. However, the circuitry underlying the antiparkinsonian action of DOP receptor agonists and their site of action have never been adequately investigated. Systemic administration of the DOP receptor agonist (+)-4-[(alphaR)-alpha-(2S,5R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide (SNC-80) attenuated akinesia/bradykinesia and improved motor activity in 6-hydroxydopamine hemilesioned rats. Opposite effects were produced by the selective DOP receptor antagonist naltrindole (NTD), suggesting that endogenous enkephalins tonically sustain movement under parkinsonian conditions. Microdialysis revealed that SNC-80 reduced GABA release in globus pallidus (GP) while NTD elevated it. Moreover, SNC-80 reduced GABA and glutamate release in substantia nigra reticulata (SNr) whereas NTD reduced GABA without affecting glutamate release. The bar test coupled to microdialysis showed that perfusion with NTD in SNr but not GP or striatum prevented the antiakinetic effect of systemic SNC-80 and its neurochemical correlates. Consistently, microinjections of SNC-80 into SNr or bicuculline in GP attenuated parkinsonian-like symptoms while SNC-80 microinjections in GP or striatum were ineffective. This study demonstrates that nigral DOP receptors mediate antiparkinsonian actions of SNC-80 and challenges the common view that DOP receptor agonists solely attenuate parkinsonism via pallidal mechanisms.
Mabrouk
Omar S
OS
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Volta
Mattia
M
Marti
Matteo
M
Morari
Michele
M
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001549:Benzamides / Q000008:administration & dosage; D001640:Bicuculline / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D019417:Hindlimb Suspension / Q000379:methods; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D010879:Piperazines / Q000008:administration & dosage; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C532500:6-(4-nitrophenyl)-2-phenyl-4-(thiophen-2-yl)-3,5-diazabicyclo(3.1.0)hex-2-ene; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018756:GABA Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; D013876:Thiophenes; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D001640:Bicuculline