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 13 micromol kg-1, s.c.) caused dose-dependent and equipotent inhibitions of both phases of
formalin-induced
pain. In contrast, in domethacin (2.7 to 27 micromol 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 within domethacin 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.