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.

Keywords: chemokine; corticotropin-releasing factor; endogenous opioids; endothelin; fever; prostaglandin; substance P.

Figure 1.

Effect of anti-CCL3 antibody on the febrile response evoked by S. aureus. The anti-CCL3 antibody was injected intracerebroventricularly at a dose of 10 ng, both 15 min and 1 h before an intraperitoneal challenge (time 0 h) with 10¹⁰ CFU of S. aureus. Body temperature (Tb) was measured with a battery-operated biotelemetry transmitter in male Wistar rats, weighing 200 g. The data were analyzed using 2-way repeated-measures analysis of variance, followed by the Bonferroni post hoc test. The data are expressed as the mean ± SEM of the change in Tb (ΔTb, °C) for each treatment, and n indicates the number of animals in each group. *p < 0.05, compared with saline (SAL)/S. aureus group. (Martins JM , Soares DM, Souza GEP, unpublished results).

Figure 2.

CCL2 does not increase rectal temperature but induces cell migration in rats. (A) Male Wistar rats received an intracerebroventricular injection of 1 μl of saline (SAL) or CCL2 (5, 50, 250, and 500 ng), and body temperature (Tb) was measured by a tele-thermistor probe coupled to a thermometer for 6 h. (B) Male Wistar rats were euthanized 6 h after an intraperitoneal injection of 50 or 500 μg CCL2, and the peritoneal content was collected. Cells from the peritoneal cavity were collected by an injection of 10 ml phosphate-buffered saline. The abdomens were gently massaged, and a blood-free cell suspension was carefully withdrawn with a syringe. The abdominal lavage was placed in plastic tubes, and total cell counts were immediately performed in a Neubauer chamber. The data were analyzed using one way or 2-way repeated-measures analysis of variance, followed by the Bonferroni post hoc test. The data are expressed as the mean ± SEM of the changes in body temperature (A, ΔTb, °C) or number of cells per mm³ (B), and n indicates the number of animals in each group. *p < 0.05, compared with the control group (Soares DM and Souza GEP, unpublished results).

Figure 3.

Proposed main central pathways that are activated during fever. The left side shows the prostaglandin-dependent pathways that are activated by TNF-α, CCL5, CXCL1, IL-1β, and IL-6. The right side shows the prostaglandin-independent pathways that are activated by PFPF, CXCL8, CCL3, and CCL4. CRF release may be a key mediator of the integration of both pathways directly or through the release of ET-1 and endogenous opioids (EOp). Dashed arrows represent pathways that have not been thoroughly investigated. Substance P was omitted because its role in these pathways has not yet been elucidated.

Figure 4.

Effects of acetaminophen on the febrile response evoked by ET-1 and Tsv. Acetaminophen (230 mg/kg, p.o.) or vehicle (Veh; 10% ethanol in saline plus 2 µl of Tween 80) was administered 30 min before an intracerebroventricular injection of ET-1 (1 pmol, A) or by an intraperitoneal injection of Tsv (150 µg/kg, B), or the same volume of saline (SAL). Body temperature (Tb) was measured by a tele-thermistor probe coupled to a thermometer for 6 h in male Wistar rats, weighing 200 g. The data were analyzed using 2-way repeated-measures analysis of variance followed by the Bonferroni post hoc test. The data are expressed as the mean ± SEM of the change in for each treatment Tb (ΔTb, °C), and n indicates the number of animals in each group. *p < 0.05, compared with Veh/ET-1 or Veh/Tsv group (De Moraes LA, Melo MCC, Souza GEP, unpublished results).