TNF-α and IL-1β mediate inflammatory hypernociception in mice triggered by B, but not B2 kinin receptor

Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B-1 and B-2 kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. Mechanical hypernociception was detected with an electronic pressure meter paw test in mice and cytokines were measured by ELISA. It was observed that in naive mice a B2 (D-Arg-Hyp(3), D-Phe(7)-bradykinin) but not a B-1 kinin receptor antagonist (des-Arg(9)-[Leu(8)]-bradykinin, DALBK) inhibited bradykinin- and carrageenin-induced hypernociception. Bradykinin-induced hypernociception was inhibited by indomethacin (5 mg/kg) and guanethidine (30 mg/kg), while not affected by IL-1ra (10 mg/kg) or antibody against keratinocyte-derived chemokine (KC/CXCL-1, 500 ng/paw) or in TNFR1 knockout mice. By contrast, in previously lipopolysaccharide (LPS)-primed mouse paw, B-1 but not B-2 kinin receptor antagonist inhibited bradykinin hypernociception. Furthermore, B-1 kinin receptor agonist induced mechanical hypernociception in LPS-primed mice, which was inhibited by indomethacin, guanethidine, antiserum against TNF-alpha or IL-1ra. This was corroborated by the induction of TNF-alpha and IL-1 beta release by B-1 kinin receptor agonist in LPS-primed mouse paws. Moreover, B-1 but not B-2 kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1 beta release as well, in LPS-primed mice. These results suggest that in naive mice the B-2 kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B-1 kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1 beta, which could stimulate prostanoid and sympathetic amine production. (c) 2007 Elsevier B.V. All rights reserved.