title: Evidence for activation of the tissue kallikrein-kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor.
abstract: The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2, 4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein specific inhibitor, was assessed using models of nociception and inflammation in mice. Injection of TKI (13.6 - 136 micromol kg(-1), i.p. or 41 - 410 micromol kg(-1), s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 micromol kg(-1), i.p.) was maximal after 30 min injection and lasted for 120 min. The effect was unaltered by pretreatment with naloxone (8.2 micromol kg(-1), s.c.) or bilateral adrenalectomy. TKI (41 and 136 micromol kg(-1), i.p.) produced a dose-related decrease of the late phase of formalin-induced nociception by 79 and 98%, respectively. At 136 micromol kg(-1), i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 micromol kg(-1), i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). TKI (41 micromol kg(-1), i.p. or 410 micromol kg(-1), s.c.) reduced the oedematogenic response, from the second to the fifth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. Pretreatment with TKI (41 micromol kg(-1), i.p.) reduced the capsaicin-induced neurogenic inflammation in the mouse ear by 54%. It is concluded that TKI presents antinociceptive and antiinflammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and inflammatory processes in mice.
authors.affiliation: Department of Pharmacology, Natural Products Section, Universidade Federal de São Paulo, Escola Paulista de Medicina. 04044-020 Rua Três de Maio 100, São Paulo, SP, Brazil.
authors.forename: J A
authors.initials: JA
authors.lastname: da S Emim
authors.forename: C
authors.initials: C
authors.lastname: Souccar
authors.forename: M S
authors.initials: MS
authors.lastname: de A Castro
authors.forename: R O
authors.initials: RO
authors.lastname: Godinho
authors.forename: M H
authors.initials: MH
authors.lastname: Cezari
authors.forename: L
authors.initials: L
authors.lastname: Juliano
authors.forename: A J
authors.initials: AJ
authors.lastname: Lapa
mesh_terms: D000315:Adrenalectomy; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007249:Inflammation / Q000209:etiology*; D007705:Kinins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010146:Pain / Q000209:etiology*; D010538:Peritonitis / Q000188:drug therapy; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors*
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007705:Kinins; D009842:Oligopeptides; C414353:phenylacetyl-Phe-Ser-Arg-N-(2,4-dinitrophenyl)ethylenediamine; D009270:Naloxone; D020840:Tissue Kallikreins