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: J A da S Emim, C Souccar, M S de A Castro, R O Godinho, M H Cezari, L Juliano, A J Lapa
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 130 Issue 5 Pg. 1099-107 (Jul 2000) ISSN: 0007-1188 [Print] England
• PMID: 10882395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Non-Narcotic
• Anti-Inflammatory Agents, Non-Steroidal
• Enzyme Inhibitors
• Kinins
• Oligopeptides
• phenylacetyl-Phe-Ser-Arg-N-(2,4-dinitrophenyl)ethylenediamine
• Naloxone
• Tissue Kallikreins

Topics

• Adrenalectomy
• Analgesics, Non-Narcotic (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Edema (drug therapy)
• Enzyme Inhibitors (pharmacology)
• Female
• Inflammation (etiology)
• Kinins (biosynthesis)
• Male
• Mice
• Naloxone (pharmacology)
• Oligopeptides (pharmacology)
• Pain (etiology)
• Peritonitis (drug therapy)
• Tissue Kallikreins (antagonists & inhibitors)