Roles of kinin B1 and B2 receptors in skin cancer pain produced by orthotopic melanoma inoculation in mice

Background: Although bradykinin is a potent algogenic peptide, the roles of this peptide and kinin receptors in cancer pain are unclear. Aims: The present study was conducted to clarify whether kinin B-1 and B-2 receptors would be involved in pain using a mouse model of skin cancer pain. Methods: B16-BL6 melanoma cells were inoculated into the hind paw of C57BL/6 mice. Licking, an index of spontaneous pain, allodynia and hyperalgesia were observed. Expression of kinin receptor mRNAs was analyzed with reverse transcription and polymerase chain reaction. The contents of kininogen and bradykinin-related peptides were assayed with Western blotting and enzyme immunoassay, respectively. Results: Melanoma inoculation induced spontaneous licking of the melanoma-bearing paw from day 18 post-inoculation, which was inhibited by local injections of B-1 and B-2 receptor antagonists. Allodynia was briefly attenuated by B-2, but not B-1 antagonist and hyperalgesia was not inhibited by either B-1 or B-2 antagonist. Local injections of B-1 and B-2 receptor agonists increased licking behavior in melanoma-bearing, but not healthy, paw. The expression of kinin B-1, but not B-2, receptor mRNA was markedly increased in the L4/5 dorsal root ganglia on the melanoma-bearing side. Melanoma cells expressed B-1 and B-2 receptors and kininogen. The content of bradykinin and related peptides was increased in the melanoma mass as compared with healthy skin. Conclusions: Bradykinin and related peptides released from melanoma cells may cause spontaneous pain and allodynia in the melanoma-bearing paw, in which B-1 and B-2 receptors on primary afferent and melanoma cells may have different roles. (C) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.