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 mug, 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 (LTB4 receptor antagonist; 3 mg kg(-1)) or dexamethasone (0.5 mg kg(-1)) inhibited the hypersensitivity from 1 to 5 h. Furthermore, LTB4 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 LTB4 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, LTB4 is the critical nociceptive mediator.