Background Basic and clinical studies suggest that hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine-immnue pathway that functionally regulates the chronic inflammatory disease including asthma. Our previous studies showed corresponding changes of cytokines and leukotriene B.sub.4 (LTB.sub.4 ) between brain and lung tissues in antigen-challenged asthmatic rats. Here, we investigated how the increased LTB.sub.4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats. Methods Ovalbumin-sensitized rats were challenged by inhalation of antigen. Rats received vehicle, LTB.sub.4 or U75302 (a selective LTB.sub.4 BLT1 receptor inhibitor) was given via intracerebroventricular injection (i.c.v) 30 min before challenge. Lung resistance (R.sub.L ) and dynamic lung compliance (C.sub.dyn ) were measured before and after antigen challenge. Inflammatory response in lung tissue was assessed 24 h after challenge. Expression of CRH mRNA and protein in hypothalamus were evaluated by RT-PCR and Western Blot, and plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using the ELISA kits. Results Antigen challenge decreased pulmonary function and induced airway inflammation, evoked HPA axis response in sensitized rats. Administration of LTB.sub.4 via i.c.v markedly attenuated airway contraction and inflammation. Meanwhile, LTB.sub.4 via i.c.v markedly increased CORT and ACTH level in plasma before antigen challenge, and followed by further increases in CORT and ACTH levels in plasma after antigen challenge in sensitized rats. Expression of CRH mRNA and protein in hypothalamus were also significantly increased by LTB.sub.4 via i.c.v in sensitized rats after antigen challenge. These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283. Conclusions LTB.sub.4 administered via i.c.v down-regulates the airway contraction response and inflammation through activation of the HPA axis via its BLT1 receptor. This study expands our concept of the regulatory role of intracranial inflammatory mediators in inflammatory diseases including asthma. The favourable effects of LTB.sub.4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.