Evidence for activation of the tissue kallikrein-kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor

摘要

class="enumerated" style="list-style-type:decimal">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 μmol kg⁻¹, i.p. or 41–410 μmol 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 μmol 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 μmol kg⁻¹, s.c.) or bilateral adrenalectomy.TKI (41 and 136 μmol kg⁻¹, i.p.) produced a dose-related decrease of the late phase of formalin-induced nociception by 79 and 98%, respectively. At 136 μmol kg⁻¹, i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 μmol kg⁻¹, i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%).TKI (41 μmol kg⁻¹, i.p. or 410 μmol 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 μmol 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.