Endogenous antipyretics: neuropeptides and glucocorticoids.

Based on observations that fever is suppressed under several physiological circumstances the existence of endogenous antipyretically active molecules has been postulated. A large number of experimental and some clinical studies provided evidence that the neuropeptides arginine vasopressin (AVP), alpha- and gamma-melanocyte stimulating hormones (alpha-MSH, gamma-MSH) and adrenocorticotropic hormone (ACTH) as well as glucocorticoids are capable to antagonize febrile responses to pyrogens. Endogenous antipyresis is mediated by actions of these molecules within the central nervous system or, at least in some cases, by peripheral effects.

Afferent nerves are involved in the febrile response to injection of LPS into artificial subcutaneous chambers in guinea pigs.

In guinea pigs, fever was induced by injections of 100 or 10 microgram/kg lipopolysaccharide (LPS) into artificial subcutaneous chambers and analysed under the influence of the local anesthetic, ropivacaine (ROPI), which was administered into the chamber at a dose of 10 mg/kg 30 min prior to LPS. In response to injections of 100 microgram/kg LPS into the subcutaneous chambers, fever was not modified by pretreatment with ROPI. High amounts of bioactive tumor necrosis factor (TNF) alpha and interleukin-6 (IL-6) were measured in the lavage of the chambers after administration of LPS.

The role of tumor necrosis factor (TNF) in the febrile and metabolic responses of rats to intraperitoneal injection of a high dose of lipopolysaccharide.

The role of tumor necrosis factor (TNF) in the febrile and metabolic responses of rats to intraperitoneal injection of a high dose of lipopolysaccharide Injection of a high dose of lipopolysaccharide (LPS) induces a septic-shock-like state, which can be accompanied by phases of hypothermia and phases of fever. In the present study we monitored body core temperature and locomotor activity, both by remote radiotelemetry, as well as changes in food intake, body mass and water intake for 3 days after an intraperitoneal (i.p.

The role of local induction of tumor necrosis factor by LPS within a subcutaneous air pouch in the development of a febrile response in guinea pigs.

In rats, fever can be induced by injection of bacterial lipopolysaccharide (LPS) into a subcutaneous air pouch. This febrile response is in part dependent on the local action of interleukin-1beta within the pouch. In the present study, we tried to find out if this model of fever induction can be applied in guinea pigs and if the local LPS-induced formation of tumor necrosis factor-alpha (TNF-alpha) participates in the development of the febrile response.

Dose-dependent attenuation of lipopolysaccharide-fever by inhibitors of inducible nitric oxide-synthase in guinea pigs.

Different doses of aminoguanidine or S-methylisothiourea, both predominantly inhibitors of the inducible form of nitric oxide (NO)-synthase, were injected into the arterial circulation of guinea pigs alone or along with 10 microg/kg bacterial lipopolysaccharide. Doses of 10 mg/kg, 50 mg/kg or 250 mg/kg aminoguanidine per se had no influence on abdominal temperature of guinea pigs. Only the highest dose of aminoguanidine (250 mg/kg) completely suppressed the first phase of the biphasic febrile response to lipopolysaccharide-injections.

Tolerance to pyrogens.

In humans or experimental animals, the repeated confrontation with lipopolysaccharides (LPS) from gram-negative bacteria, but not with muramyl dipeptide (MDP) from gram-positive bacteria, leads to attenuation of almost all pathophysiologic effects mediated by proinflammatory cytokines. Our experiments in guinea pigs and rats demonstrate that attenuation of the febrile response during the development of LPS tolerance is associated with a reduced production of cytokines rather than a decrease in responsiveness to cytokines. Cross-tolerance experiments demonstrate that different stimuli influencing LPS-induced tumor necrosis factor (TNF) release and nitric oxide (NO) synthesis can modify the development of tolerance.

Inhibition of nitric oxide synthase attenuates lipopolysaccharide-induced fever without reduction of circulating cytokines in guinea-pigs.

It was recently demonstrated that the diffusible messenger molecule nitric oxide (NO) is involved in the febrile response of rats and rabbits to exogenous or endogenous pyrogens. In this study we have investigated the effects of systemic administration of the NO-synthase inhibitor N-nitro-l-arginine-methylester (l-NAME) on abdominal temperature and on lipopolysaccharide- (LPS-) induced fever in guinea-pigs. We further studied the effects of l-NAME on the LPS-induced circulating cytokine network by measurement of tumor necrosis factor alpha (TNF) and interleukin-6 (IL-6) in blood plasma during the time course of fever.

Biogenic amines and thermoregulatory changes.

This review recapitulates the general principles of the organization of the thermoregulatory system, describes the thermoregulatory reactions of small and large mammals to hot environment and analyzes the probable roles of biogenic amines in these responses. Catecholamines found in peripheral blood plasma or excreted in urine represent a spillover of mediators released partly from sympathetic nerve endings and partly from the adrenal medulla. Since the thermoregulatory efforts differ between small and large mammals in cold and hot environments, the peripheral release of catecholamines is also different in these animals.

Inhibition of nitric oxide synthase results in a suppression of interleukin-1beta-induced fever in rats.

Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) induce nitric oxide synthase. The purpose of this study was to investigate the role of endogenous nitric oxide in IL-1beta-induced fever in rats. At a dose of 2.

Neutralization of pyrogen-induced tumour necrosis factor by its type 1 soluble receptor in guinea-pigs: effects on fever and interleukin-6 release.

1. A soluble form of the tumour necrosis factor (TNF) type 1 receptor (referred to as TNF binding protein, TNF-bp) at a dose of 1 mg per animal, or an equivalent volume of solvent, was injected together with 10 microg kg-1 lipopolysaccharide (LPS) or 50 microg kg-1 muramyl-dipeptide (MDP) directly into the arterial circulation of guinea-pigs and the effects on circulating TNF or interleukin-6 (IL-6) and on abdominal temperature were studied. 2.

Changes of abdominal temperature and circulating levels of cortisol and interleukin-6 in response to intra-arterial infusions of tumor necrosis factor-alpha or tumor necrosis factor-beta in guinea pigs.

The sister proteins tumor necrosis factor (TNF)-alpha and TNF-beta share 35% of their amino acid sequence and a number, but not all, of their biological properties. In the present study we infused amounts of 5 microg/kg TNF-alpha, TNF-beta (both preparations with identical bioactivities) or of solvent (0.9% sterile saline) into the circulation of guinea pigs and studied the effects on abdominal temperature, on the induction of endogenous formation of interleukin-6 and on levels of cortisol in plasma as a parameter of the activation of the hypothalamic-pituitary-adrenal axis.

Lack of cross tolerance between LPS and muramyl dipeptide in induction of circulating TNF-alpha and IL-6 in guinea pigs.

In guinea pigs, lipopolysaccharide (LPS) from gram-negative bacteria and muramyl dipeptide (MDP) from gram-positive bacteria are potent inducers of systemic production of proinflammatory cytokines and fever. However, there is a striking difference between these two bacterial pyrogens in so far as repeated administration of LPS, but not of MDP, in short-term intervals induces tolerance by a progressive downregulation of the systemic cytokine network. In the present study, we investigated MDP-induced fever and the systemic release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in LPS-tolerant guinea pigs in comparison with naive animals.

Fever and production of cytokines in response to repeated injections of muramyl dipeptide in guinea-pigs.

Fever and systemic plasma levels of the cytokines tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were measured in guinea-pigs in response to single or repeated intramuscular injections of 100 micrograms/kg muramyl-dipeptide (MDP). In a pilot study (experiment 1), MDP-induced fever was monitored for 8 h. The first fever phase 90-360 min after injection of MDP was followed by the second phase which continued beyond the duration of this experiment.

Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration.

It has recently been shown that subdiaphragmatic vagotomy blocks some of the effects of inflammatory stimuli on brain-controlled functions. Therefore, vagal afferent fibers have been proposed to play a prominent role in the communication pathways between the immune system and the brain. In the present study, we investigated the effect of subdiaphragmatic vagotomy on fever induced by intraperitoneal or intramuscular injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP), which are both cytokine-inducing agents in guinea pigs.

Influence of pentoxifylline on fevers induced by bacterial lipopolysaccharide and tumor necrosis factor-alpha in guinea pigs.

In guinea pigs intraperitoneal (i.p.) injections of 50 mg/kg pentoxifylline had no influence on abdominal temperature while higher doses of pentoxifylline caused a hypothermic response lasting for 2-3 h.

Lack of tolerance development to tumor necrosis factor alpha inside the central nervous system.

Tumor necrosis factor alpha (TNF alpha) was repeatedly microinfused into the lateral ventricle of guinea pig brains at a dose of 200 ng, 4 times within 150 min, at intervals of 3 days. In comparison to guinea pigs infused with solvent according to the same time schedule. the animals responded to TNF alpha with pronounced fevers.

Repeated infusions of TNF-alpha cause attenuation of the thermal response and influence LPS fever in guinea pigs.

In conscious, freely moving guinea pigs, tumor necrosis factor (TNF)-alpha and TNF-beta, infused into the aortic arch within a period of 45 min at a dosage of 5 micrograms/kg, induced different thermal responses. TNF-alpha evoked a biphasic elevation of abdominal temperature, both phases together lasting longer than 6 h. In response to infusions of TNF-beta, the first phase, lasting approximately 120 min, was the same as was observed in response to TNF-alpha, whereas the longer second phase of temperature increase was missing.

Fever response in lean (Fa/-) and obese (fa/fa) Zucker rats and its lack to repeated injections of LPS.

The thermal responses of Fa/- and fa/fa Zucker rats to injections of sterile saline and to four injections of 20 micrograms/kg LPS at 3-day intervals were measured by means of radiotelemetry. In response to injections of saline, only the Fa/- rats developed a short stress-induced increase in abdominal temperature. Such a stress-induced rise of core temperature was also monitored in Fa/- rats after a change of the animals' cages.

Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever.

Changes in concentrations of cytokines in plasma and in hypothalamic push-pull perfusates of guinea pigs were measured within the 1st hour after intramuscular injections of bacterial lipopolysaccharide (LPS; Escherichia coli, 20 micrograms/kg) or solvent (0.9% saline). In control animals injected with solvent, interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) were not detectable in plasma.

Endotoxin tolerance alters thermal response of guinea pigs to systemic infusions of tumor necrosis factor-alpha.

In guinea pigs, intra-arterial infusions of 5 micrograms/kg tumor necrosis factor-alpha (TNF; specific activity 20,000 U/micrograms; duration of infusion 45-50 min) evoked a biphasic elevation of abdominal temperature lasting approximately 6 h. One week after systemic infusion of TNF, the animals started to receive either five intramuscular injections of bacterial lipopolysaccharide (LPS from Escherichia coli; 20 micrograms/kg) or equivalent volumes of solvent (0.9% NaCl) in intervals of 3 days.

Changes in body temperature and circulating levels of interleukin-6 after intra-arterial injections or infusions of tumor necrosis factor alpha in guinea pigs.

Tumor necrosis factor alpha (TNF) is released systematically during the early phase of endotoxin induced fever. To study the effects of this cytokine in guinea pigs, 2 micrograms TNF were intra-arterially injected as a bolus or slowly infused within 60 min. Both modes of administration induced a biphasic elevation of the animals' abdominal temperature lasting 6 h and stimulated the release of endogenous interleukin-6 (IL-6)-like activity.

Attenuation of fever and release of cytokines after repeated injections of lipopolysaccharide in guinea-pigs.

1. The effects of repeated injections of bacterial lipopolysaccharide (LPS) at 3 day intervals on abdominal temperature and systemic release of tumour necrosis factor alpha (TNF)-like and interleukin-6 (IL-6)-like activity were measured in guinea-pigs. 2.