The critical role of leukotriene B 4 in antigen-induced mechanical hyperalgesia in immunised rats

Abstract

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 μg, 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 TNFα, IL-1β 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-TNFα, IL-1β 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 3h, 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 TNFα-, IL-1β- 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 TNFα has some role, LTB 4 is the critical nociceptive mediator.