No abstract

Kanashiro A, Pessini AC, Machado RR, Malvar DC, Aguiar FA, Soares DM, Vale ML, Souza GEP. Characterization and pharmacological evaluation of febrile response on zymosan-induced arthritis in rats. Am J Physiol Regul Integr Comp Physiol 296: R1631-R1640, 2009. First published February 25, 2009 doi:10.1152/ajpregu.90527.2008.-The present study investigated the febrile response in zymosan-induced arthritis, as well as the increase in PGE2 concentration in the cerebrospinal fluid (CSF), along with the effects of antipyretic drugs on these responses in rats. Zymosan intra-articularly injected at the dose of 0.5 mg did not affect the body core temperature (Tc) compared with saline (control), whereas at doses of 1 and 2 mg, zymosan promoted a flattened increase in Tc and declined thereafter. The dose of 4 mg of zymosan was selected for further experiments because it elicited a marked and long-lasting Tc elevation starting at 3 1/2 h, peaking at 5 1/2 h, and remaining until 10 h. This temperature increase was preceded by a decrease in the tail skin temperature, as well as hyperalgesia and edema in the knee joint. No febrile response was observed in the following days. In addition, zymosan-induced fever was not modified by the sciatic nerve excision. Zymosan increased PGE 2 concentration in the CSF but not in the plasma. Oral pretreatment with ibuprofen (5-20 mg/kg), celecoxib (1-10 mg/kg), dipyrone (60 -240 mg/kg), and paracetamol (100 -200 mg/kg) or subcutaneous injection of dexamethasone (0.25-1.0 mg/kg) dose-dependently reduced or prevented the fever during the zymosan-induced arthritis. Celecoxib (5 mg/kg), paracetamol (150 mg/kg), and dipyrone (120 mg/kg) decreased CSF PGE 2 concentration and fever during zymosan-induced arthritis, suggesting the involvement of PGE2 in this response.

BACKGROUND AND PURPOSEBacterial lipopolysaccharide (LPS) induces fever through two parallel pathways; one, prostaglandin (PG)-dependent and the other, PG-independent and involving endothelin-1 (ET-1). For a better understanding of the mechanisms by which dipyrone exerts antipyresis, we have investigated its effects on fever and changes in PGE2 content in plasma, CSF and hypothalamus induced by either LPS or ET-1. EXPERIMENTAL APPROACHRats were given (i.p.) dipyrone (120 mg·kg , i.v.) or ET-1 (1 pmol, i.c.v.). Rectal temperature was measured by tele-thermometry. PGE2 levels were determined in the plasma, CSF and hypothalamus by ELISA. KEY RESULTSLPS or ET-1 induced fever and increased CSF and hypothalamic PGE2 levels. Two hours after LPS, indomethacin reduced CSF and hypothalamic PGE2 but did not inhibit fever, while at 3 h it reduced all three parameters. Three hours after ET-1, indomethacin inhibited the increase in CSF and hypothalamic PGE2 levels but did not affect fever. Dipyrone abolished both the fever and the increased CSF PGE2 levels induced by LPS or ET-1 but did not affect the increased hypothalamic PGE2 levels. Dipyrone also reduced the increase in the venous plasma PGE2 concentration induced by LPS. CONCLUSIONS AND IMPLICATIONSThese findings confirm that PGE2 does not play a relevant role in ET-1-induced fever. They also demonstrate for the first time that the antipyretic effect of dipyrone was not mechanistically linked to the inhibition of hypothalamic PGE2 synthesis.

This study evaluated the participation of -opioid-receptor activation in body temperature (T b) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid -receptor-antagonist cyclic D-Phe-Cys-Try-DTrp-Arg-Thr-Pen-Thr-NH2 (CTAP; 0.1-1.0 g) reduced fever induced by LPS (5.0 g/kg) but did not change Tb at ambient temperatures of either 20°C or 28°C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0 -10.0 mg/kg, 3.0 -30.0 g, and 1-100 ng, respectively) produced a dose-dependent increase in Tb. Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 g icv) reduced the fever induced by intracerebroventricular administration of TNF-␣ (250 ng), IL-6 (300 ng), CRF (2.5 g), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF2␣ (500.0 ng) but not the fever induced by IL-1␤ (3.12 ng) or PGE2 (125.0 ng) or the second phase of the fever induced by PGF2␣. Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE2 levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1␤ and prostaglandins) recruit the opioid system to cause a -receptor-mediated fever. prostaglandin independent; body temperature; morphine; CTAP THE REGULATION OF BODY TEMPERATURE (T b ) is under the control of a hierarchy of neuronal structures that must first integrate afferent and central information before activating appropriate physiological and behavioral responses. In mammals, T b is regulated with considerable precision, normally varying by only a few degrees Celsius. This is an important adaptation because most biochemical and physiological processes are temperature dependent. In some conditions, adjustments of T b are beneficial. During infection, an increase in T b (fever) enhances immunologic responses and facilitates recovery and survival of an individual (34). In other conditions (such as during hypoxia), a decrease in T b is also beneficial because lower T b increases survival, primarily through a reduction in metabolic rate (13,38). The preoptic area of anterior hypothalamus (POA-AH) is one of the major neuronal structures involved in the control of T b . In addition to receiving afferent input from peripheral thermoreceptors, the POA-AH responds to central changes in hypothalamic temperature (10).Fever is characterized as a controlled elevation in the thermal set point, which is induced initially by exogenous pyrogens. These exogenous pyrogens induce the synthesis and release of a number of endogenous pyrogens, including IL-1␤, TNF...