Altered extracellular striatal in vivo biotransformation of the opioid neuropeptide dynorphin A(1-17) in the unilateral 6-OHDA rat model of Parkinson's disease.
The in vivo biotransformation of dynorphin A(1-17) (Dyn A) was studied in the striatum of hemiparkinsonian rats by using microdialysis in combination with nanoflow reversed-phase liquid chromatography/electrospray time-of-flight mass spectrometry. The microdialysis probes were implanted into both hemispheres of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. Dyn A (10 pmol microl(-1)) was infused through the probes at 0.4 microl min(-1) for 2 h. Samples were collected every 30 min and analyzed by mass spectrometry. The results showed for the first time that there was a difference in the Dyn A biotransformation when comparing the two corresponding sides of the brain. Dyn A metabolites 1-8, 1-16, 5-17, 10-17, 7-10 and 8-10 were detected in the dopamine-depleted striatum but not in the untreated striatum. Dyn A biotransformed fragments found in both hemispheres were N-terminal fragments 1-4, 1-5, 1-6, 1-11, 1-12 and 1-13, C-terminal fragments 2-17, 3-17, 4-17, 7-17 and 8-17 and internal fragments 2-5, 2-10, 2-11, 2-12, and 8-15. The relative levels of these fragments were lower in the dopamine-depleted striatum. The results imply that the extracellular in vivo processing of the dynorphin system is being disturbed in the 6-OHDA-lesion animal model of Parkinson's disease.
Klintenberg
Rebecka
R
Laboratory for Biological and Medical Mass Spectrometry and Department of Pharmaceutical Biosciences, Uppsala University, Box 583, SE-75123 Uppsala, Sweden.
Andrén
Per E
PE
D000595:Amino Acid Sequence; D000818:Animals; D001058:Apomorphine; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism*; D004195:Disease Models, Animal; D004399:Dynorphins / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D013058:Mass Spectrometry / Q000379:methods; D017551:Microdialysis; D008969:Molecular Sequence Data; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
D010446:Peptide Fragments; D004399:Dynorphins; D016627:Oxidopamine; D001058:Apomorphine