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

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. British Journal of Pharmacology (2000) 130, 1099–1107; doi:10.1038/sj.bjp.0703362