In view of the potential involvement of peripherally synthesized, circulating amphipathic mediators [such as platelet-activating factor (PAF) and prostaglandin E₂] in the systemic inflammatory response to lipopolysaccharide (LPS), we hypothesized that transport of amphipaths by albumin is essential for conveying peripheral inflammatory signals to the brain. Our first specific aim was to test this hypothesis by studying LPS-induced fever and hypothermia in Nagase analbuminemic rats (NAR). NAR from two different colonies and normalbuminemic Sprague-Dawley (SD) rats were preimplanted with jugular catheters, and their febrile responses to a mild dose of LPS (10 µg/kg iv) at thermoneutrality and hypothermic responses to a high dose of LPS (500 µg/kg iv) in the cold were studied. NAR of both colonies developed normal febrile and hypothermic responses, thus suggesting that transport of amphipathic mediators by albumin is not indispensable for LPS signaling. Although alternative carrier proteins [such as ₁-acid glycoprotein (AGP)] are known to assume transport functions of albumin in NAR, it is unknown whether inflammatory mediators are capable of inducing their actions when bound to alternative carriers. To test whether PAF, the most potent amphipathic pyrogen, causes fever when administered in an AGP-bound form was our second aim. SD rats were preimplanted with jugular catheters, and their thermal responses to infusion of a 1:1 [PAF-AGP] complex (40 nmol/kg iv), AGP (40 nmol/kg iv), or various doses of free (aggregated) PAF were studied. The complex, but neither free PAF nor AGP, caused a high (~1.5°C) fever with a short (< 10 min) latency. This is the first demonstration of a pyrogenic activity of AGP-bound PAF. We conclude that, in the absence of albumin, AGP and possibly other carriers participate in immune-to-brain signaling by binding and transporting amphipathic inflammatory mediators.