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

We investigated the mediators responsible for mechanical hypersensitivity induced by antigen challenge in rats immunised with ovalbumin (OVA). Challenge with OVA (12.5–100 μ g, intraplantar) caused a dose‐ and time‐dependent mechanical hypersensitivity, which peaked 3 h after, decreased thereafter and reached control levels 24 h later. Levels of TNF α , IL‐1 β and cytokine‐induced neutrophil chemoattractant 1 (CINC‐1) were increased in paw skin after antigen challenge. OVA‐evoked hypersensitivity was partially inhibited (about 51%) by pretreatment with anti‐TNF α , IL‐1 β 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. 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. 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. In conclusion, our results suggest that the TNF α ‐, IL‐1 β ‐ 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 TNF α has some role, LTB 4 is the critical nociceptive mediator.British Journal of Pharmacology (2003) 139 , 1135–1145. doi: 10.1038/sj.bjp.0705346