title: Central mediators involved in the febrile response: effects of antipyretic drugs.
abstract: Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1β, tumor necrosis factor-α, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions.
authors.affiliation: Department of Pharmacology; Biological Sciences Section; Federal University of Paraná ; Curitiba, PR, Brazil.
authors.forename: Aleksander R
authors.initials: AR
authors.lastname: Zampronio
authors.affiliation: Department of Medicament; Faculty of Pharmacy; Federal University of Bahia ; Salvador, BA, Brazil.
authors.forename: Denis M
authors.initials: DM
authors.lastname: Soares
authors.affiliation: Discipline of Pharmacology; Faculty of Pharmaceutical Sciences of Ribeirão Preto; University of São Paulo ; Ribeirão Preto, SP, Brazil.
authors.forename: Glória E P
authors.initials: GE
authors.lastname: Souza
keywords: chemokine; corticotropin-releasing factor; endogenous opioids; endothelin; fever; prostaglandin; substance P