title: Modification by the tissue plasminogen activator-plasmin system of morphine-induced dopamine release and hyperlocomotion, but not anti-nociceptive effect in mice.
abstract: The extracellular serine protease tissue plasminogen activator (tPA) that converts plasminogen into plasmin is abundantly expressed throughout the central nervous system. We have recently demonstrated that the tPA-plasmin system participates in the rewarding and locomotor-stimulating effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAc). In the present study, we examined the effects of microinjections of plasminogen activator inhibitor-1 (PAI-1), tPA or plasmin into the NAc on morphine-induced dopamine release, hyperlocomotion and anti-nociceptive effects in ICR mice. A single morphine treatment resulted in an increase in protein levels of PAI-1 in the NAc. Microinjection of PAI-1 into the NAc dose-dependently reduced morphine-induced dopamine release and hyperlocomotion. In contrast, microinjection of tPA into the NAc significantly potentiated morphine-induced dopamine release and hyperlocomotion without affecting basal levels. Furthermore, microinjection of plasmin enhanced morphine-induced dopamine release, but did not modify the hyperlocomotion induced by morphine. The intracerebroventricular injection of PAI-1, tPA and plasmin at high doses had no effect on the anti-nociceptive effects of morphine. These results suggest that the tPA-plasmin system is involved in the regulation of morphine-induced dopamine release and dopamine-dependent behaviors but not the anti-nociceptive effects of morphine.
authors.affiliation: Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamei
authors.forename: Mina
authors.initials: M
authors.lastname: Ito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D005341:Fibrinolysin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D009294:Narcotics; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D009020:Morphine; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D004298:Dopamine