The critical role of leukotriene B4 in antigen-induced mechanical hyperalgesia in immunised rats.
1. We investigated the mediators responsible for mechanical hypersensitivity induced by antigen challenge in rats immunised with ovalbumin (OVA). 2. Challenge with OVA (12.5-100 micro g, intraplantar) caused a dose- and time-dependent mechanical hypersensitivity, which peaked 3 h after, decreased thereafter and reached control levels 24 h later. 3. Levels of TNFalpha, IL-1beta and cytokine-induced neutrophil chemoattractant 1 (CINC-1) were increased in paw skin after antigen challenge. 4. OVA-evoked hypersensitivity was partially inhibited (about 51%) by pretreatment with anti-TNFalpha, IL-1beta and IL-8 sera or with IL-1 receptor antagonist (IL-1ra), but not anti-NGF serum. Pretreatment with thalidomide (45 mg kg(-1)) or pentoxifylline (100 mg kg(-1)) also partially inhibited the hypersensitivity at 1-3 h after challenge. 5. Pretreatment with indomethacin (5 mg kg(-1)) or atenolol (1 mg kg(-1)) reduced the OVA-induced hypersensitivity at 1 and 3 h, but not at 5 h after challenge, while the combination of B(1) and B(2) bradykinin receptor antagonists was ineffective over the same times. 6. Pretreatment with MK886 (5-lipoxygenase-activating protein inhibitor, 3 mg kg(-1)), CP 105696 (LTB(4) receptor antagonist; 3 mg kg(-1)) or dexamethasone (0.5 mg kg(-1)) inhibited the hypersensitivity from 1 to 5 h. Furthermore, LTB(4) levels were increased in the paw skin of challenged rats. 7. In conclusion, our results suggest that the TNFalpha-, IL-1beta- and CINC-1-driven release of prostaglandins, sympathetic amines and LTB(4) mediates the first 3 h of mechanical hypersensitivity induced by antigen challenge in rats. At 5 h after OVA administration, although TNFalpha has some role, LTB(4) is the critical nociceptive mediator.
Cunha
Joice Maria
JM
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
Sachs
Daniela
D
Canetti
Cláudio Azevedo
CA
Poole
Stephen
S
Ferreira
Sérgio Henrique
SH
Cunha
Fernando Queiroz
FQ
D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D006930:Hyperalgesia / Q000276:immunology* / Q000378:metabolism*; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D007279:Injections, Subcutaneous; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010147:Pain Measurement / Q000379:methods; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D000941:Antigens; D007975:Leukotriene B4; D010047:Ovalbumin