Immune-mediated febrile response in female rats: Role of central hypothalamic mediators

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor κB ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 μg/kg) intraperitoneally or CRF (2.5 μg), ET-1 (1 pg), morphine (10 μg) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 μg, intracerebroventricularly). Expression of RANK, CRF_I/II, ET_B, μ-opioid (MOR) and NK₁ receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.