TNF-alpha and IL-1beta mediate inflammatory hypernociception in mice triggered by B1 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 naïve mice a B(2) (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-1beta 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-1beta release as well, in LPS-primed mice. These results suggest that in naïve 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-1beta, which could stimulate prostanoid and sympathetic amine production.
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Thiago M
TM
Cunha
Waldiceu A
WA
Verri
Sandra Y
SY
Fukada
Ana T G
AT
Guerrero
Tania
T
Santodomingo-Garzón
Stephen
S
Poole
Carlos A
CA
Parada
Sergio H
SH
Ferreira
Fernando Q
FQ
Cunha
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D065168:Bradykinin Receptor Antagonists; D002351:Carrageenan / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006145:Guanethidine / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D053583:Interleukin-1beta / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011453:Prostaglandins / Q000502:physiology; D043783:Receptor, Bradykinin B1 / Q000819:agonists / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D018002:Receptors, Bradykinin / Q000819:agonists / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D065168:Bradykinin Receptor Antagonists; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011453:Prostaglandins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C051090:bradykinin, Leu(8)-des-Arg(9)-; D002351:Carrageenan; D001920:Bradykinin; D007213:Indomethacin; D006145:Guanethidine