title: Phenylmethanesulfonyl fluoride, a serine protease inhibitor, suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice.
abstract: We have previously shown that intracerebroventricular (i.c.v.) administration of cysteine protease inhibitors suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation (see (Tan-No, K., Sato, T., Shimoda, M., Nakagawasai, O., Niijima, F., Kawamura, S., Furuta, S., Sato, T., Satoh, S., Silberring, J., Terenius, L., Tadano, T., 2010. Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice. Neuropeptides 44, 279-283)). In the present study, we examined the effect of phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, on naloxone-precipitated withdrawal jumping in morphine-dependent mice. The doses of morphine (mg/kg per injection) were subcutaneously given twice daily for 2 days [day 1 (30) and day 2 (60)]. On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3h after the final injection of morphine (60 mg/kg), and the number of jumps was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by i.c.v. administration of PMSF (4 nmol), given 5 min before each morphine treatment during the induction phase, with none given on the test day. The expression of tissue plasminogen activator (tPA), a serine protease that converts plasminogen to plasmin, in the prefrontal cortex was significantly increased in morphine-dependent and -withdrawal mice, as compared with saline-treated mice. Moreover, trans-4-(aminomethyl)-cyclohexanecarboxylic acid (300 pmol), an antiplasmin agent, and (Tyr(1))-thrombin receptor activating peptide 7 (0.45 and 2 nmol), an antagonist of protease activated receptor-1 (PAR-1), significantly suppressed naloxone-precipitated withdrawal jumping. The present results suggest that PMSF suppresses naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of activities of tPA and plasmin belonging to the serine proteases family, which subsequently activates PAR-1.
authors.affiliation: Department of Pharmacology, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nemoto
authors.forename: Tasuku
authors.initials: T
authors.lastname: Sato
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakagawasai
authors.forename: Fukie
authors.initials: F
authors.lastname: Yaoita
authors.forename: Jerzy
authors.initials: J
authors.lastname: Silberring
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tadano
authors.forename: Koichi
authors.initials: K
authors.lastname: Tan-No
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000523:psychology*; D009270:Naloxone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000523:psychology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014148:Tranexamic Acid / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: D009292:Narcotic Antagonists; D015842:Serine Proteinase Inhibitors; D009270:Naloxone; D010664:Phenylmethylsulfonyl Fluoride; D014148:Tranexamic Acid; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D010975:Platelet Aggregation Inhibitors