However, it has been shown by others that SP does participate in LPS-induced Trichostatin A in vitro fever (Blatteis et al., 1994 and Szelenyi et al., 1997). These studies already indicated that centrally released SP could be important for the febrile response using other antagonists.
Indeed, there is evidence for the particularly high expression of SP receptors in the rat hypothalamus, a region critically involved in temperature control and fever responses (Tsuchida et al., 1990). Also, there is evidence for the presence of SP and its precursor preprotachykinin A in the hypothalamus of primates and rats (Gautreau and Kerdelhue, 1998 and Hurd et al., 1999). Therefore, selleck compound all the functional requirements for the local formation, release and action of SP appear to be present in the hypothalamus. In addition, the efficacy of centrally injected SR140333B in reducing LPS-induced fever would suggest that this pyrogen raises central SP levels. Thus, LPS may promptly mobilize SP and the participation of the latter in fever induction by this agent appears to be essential to the process since the blockade of the response by the centrally administered NK1R antagonist SR140333B is evident from the onset of the fever. LPS is a potent stimulus for SP production and secretion both
peripherally (Ng et al., 2008 and Wang et al., 2008) and also in the spinal cord (Bret-Dibat et al., 1994). Thus, since SP increases body temperature in rats and guinea pigs (Blatteis et al., 1994 and Szelenyi et al., 1997), the ability of LPS to trigger SP-mediated fever is not entirely unexpected. On the other hand, the induction of fever only in captopril-treated rats is somehow different from what was reported previously. In fact, we actually observed that the temperature variation among the animals injected with SP alone was quite high in our experience with fever induction. This raised the possibility
that variations in SP metabolism among the animals could trigger the observed temperature variation. Ribonucleotide reductase Angiotensin-converting enzyme (ACE) has been reported to be among the enzymes that metabolize SP (Skidgel and Erdos, 2004). Since the majority of ACE inhibitors, including captopril, do not cross the blood–brain barrier we decided to inject it directly into the brain. The treatment of the animals with this drug allowed us to observe a more consistent effect of SP in causing fever. However, it is also known that bradykinin can induce fever (Coelho et al., 1997) and, therefore, the febrile response observed after captopril injection could be a result of an increase in bradykinin levels due to ACE inhibition.