Evidence for participation of B1 and B2 kinin receptors in formalin‐induced nociceptive response in the mouse

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Abstract
1 This study was designed to investigate the role of bradykinin (BK), as well as the subtype of BK receptors involved, in formalin-induced hindpaw pain in the mouse by use of selective B1 and B2 receptor antagonists. In addition, we have analysed whether or not BK may be involved in formalin-induced hindpaw oedema in the mouse. 2 The pretreatment of animals with captopril (2 and 5 mg kg−1, s.c.) significantly increase the first and the second phases of formalin-induced pain. 3 Co-injection of the selective B1 receptor antagonist des-Arg9[Leu8]-BK (0.2–0.4 nmol/paw), together with formalin, caused graded and similar inhibitions of both phases of formalin-induced pain. Similar results were obtained with the B2 antagonists NPC 349 (d-Arg[Hyp3,Thi5,8-d-Phe7]-BK) and NPC 567 (d-Arg[Hyp3, d-Phe7]-BK) (0.2 and 0.6 nmol/paw). Higher concentrations of these antagonists (1 nmol/paw) failed to antagonize formalin-induced pain. 4 The new potent and selective B2 receptor antagonists, Hoe 140 (d-Arg[Hyp3,Thi5,d-Tic7,Oic8]-BK), NPC 17731 (d-Arg[Hyp3, trans-4-propoxy-d-proline (transpropyl)7, Oic8]-BK), and NPC 17761 (d-Arg[Hyp3, trans-4-propoxy-d-proline (trans thiophenyl)7, Oic8]-BK) (0.02 to 1.0 nmol/paw), also caused significant inhibitions of both phases of formalin-induced pain. When Hoe 140 was injected subcutaneously 30 min before formalin injection (9.9 and 99 nmol kg−1), it significantly attenuated both phases of formalin-induced pain. The putative non-peptide BK antagonist, MV 8612 (1.6 to 9.6 nmol/paw), but not MV 8608 (5.5 to 33 nmol/paw), caused a graded inhibition of both phases of formalin-induced pain, being, however, more active against the first phase. 5 The pretreatment of animals with morphine (2.6 to 13μmol kg−1, s.c.) caused dose-dependent and equipotent inhibitions of both phases of formalin-induced pain. In contrast, indomethacin (2.7 to 27 μmol kg−1) antagonized only the second phase of formalin-induced pain. 6 The B2 receptor antagonists, Hoe 140, NPC 17731, NPC 17761, NPC 349 and NPC 567, all caused a significant inhibition of formalin-induced hindpaw oedema. A similar inhibition was also observed with indomethacin but not with captopril or morphine. 7 Our results provide strong evidence for the important role of endogenous BK, acting through both B1 and B2 receptors, in the genesis of both phases of formalin-induced persistent pain in the mouse. In addition, the current results also demonstrate that the inflammatory oedema associated with the later phase of formalin-induced pain seems to be mediated by endogenous BK, via activation of B2 receptors.