Restraint increases afebrile body temperature but attenuates fever in Pekin ducks (Anas platyrhynchos)

In mammals, procedures such as handling, restraint, or exposure to open spaces induces an increase in body temperature (Tb). The increase in temperature shares some characteristics with pyrogen-induced fever and so is often called “stress fever.” Birds also respond to acute handling with a stress fever, which may confound thermoregulatory studies that involve animal restraint. We have measured the Tb responses of Pekin ducks on days when they were restrained and compared them to days when the birds remained unrestrained. Restraint induced a 0.5°C increase in Tb that was sustained for the entire 8 h of restraint. To determine whether the restraint-induced increase in Tb is mediated by prostaglandins (PGs) we compared the Tb responses during restraint after intraperitoneal injection with saline to the responses during restraint after injection with diclofenac sodium (15 mg/kg). There was no difference in response, suggesting that restraint affects Tb by a PG-independent mechanism. We also compared the Tb response to intramuscular injection of lipopolysaccharide (LPS; 100 μg/kg), a bacterial pyrogen, when the ducks were restrained or unrestrained. Despite Tb being higher at the time of LPS injection when the ducks were restrained, the maximum temperature reached after LPS injection was higher, and the period that Tb remained elevated was longer when the ducks were unrestrained. We conclude that restraint should be considered as a potential confounder in thermoregulatory studies in birds and presumably other species too.

Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells

Lipopolysaccharide (LPS), a well-known bacterial pyrogen, is recognized by several receptors, including the Toll-like receptor 4 (TLR4), on various cells. Which of these receptors and cells are linked to fever production is unknown. By constructing 4 mouse chimeras and studying their thermoregulatory responses, we found that all 3 phases of the typical LPS fever depend on TLR4 signaling. The first phase is triggered via the TLR4 on hematopoietic cells. The second and third phases involve TLR4 signaling in both hematopoietic and nonhematopoietic cells.

Anatomical distribution of brainstem sites where PGE1 induces hyperthermia in macaque species

The neuroanatomical distribution of sites in the diencephalon and mesencephalon within which a prostaglandin (PG) of the E series elicits hyperthermia was characterized in Macaca mulatta and Macaca nemestrina. In 420 experiments undertaken in 13 animals, 225 loci were examined for their reactivity to PGE1 microinjected in a dose of 30 or 100 ng given in a volume of 1.0–1.5 μL. The regions of the brainstem for injection extended rostrally from the thermosensitive cells of the anterior hypothalamic, preoptic area (AH/POA) to the caudal border of the mesencephalon. Colonic and skin temperatures of the monkeys were measured continuously by thermistor probes. A hyperthermic response of ≥0.5 °C and a latency of ≤45 min was evoked by PGE1 within sites located primarily in the AH/POA. When PGE1 was microinjected at loci located caudal to the AH/POA, the elevation in body temperature (Tb) not only was less intense but rose at a slower rate. A higher concentration of PGE1 in these caudal regions was required to induce hyperthermia comparable with that elicited at loci within the AH/POA. In a second series of experiments either 1.0–5.0 μg 5-hydroxytryptamine (serotonin) or a concentration of 108 organisms/mL of Escherichia coli was microinjected at PGE1-reactive sites. A close anatomical concordance within the AH/POA of the animal was found in terms of the temporal characteristics and magnitude of the hyperthermia evoked by the indoleamine or lipopolysaccharide. The present results coincide with the reported neuroanatomical distribution of sites in the diencephalon and mesencephalon of other species in which PGE1 causes hyperthermia. Furthermore, these findings support the concept that the local neuronal mechanism of action of a pyrogen in the brainstem of the primate may involve phasic changes in the endogenous activity of both the serotonergic pathway and cyclo-oxygenase system in the AH/POA. In turn, their commonality of action suggests a functional similarity in their effect of shifting the set point for Tb.Key words: prostaglandin E1, hyperthermia, serotonin, Escherichia coli, anterior hypothalamus, thermoregulation, bacterial pyrogen, preoptic area, neuroanatomical localization, Macaca nemestrina, Macaca mulatta.

Vasopressin and fever: evidence supporting the existence of an endogenous antipyretic system in the brain

Vasopressin administered into the ventral septum exerts a dose-related antipyresis. This site of action is similar in a number of species. The fever-reducing properties of vasopressin are both site and neuropeptide specific. Evidence supporting a role for endogenous vasopressin in fever suppression is the demonstration that the release of the peptide from the ventral septal area is altered during fever: the amount released correlates negatively with febrile changes in body temperature. In addition, changes in the concentration of vasopressin in the septum and amygdala have been demonstrated immunocytochemically during fever: an activation of vasopressinergic neurons occurs which is similar to that observed in pregnant animals at term when fever is absent. Specific antibodies directed against vasopressin or specific vasopressin antagonist analogues (e.g., d(CH2)5Tyr(Me)AVP) enhanced the febrile response to a pyrogen challenge when injected into the ventral septum. The same antagonist also can antagonize the antipyretic effect of exogenously administered vasopressin. The use of relatively specific antagonists and agonists of vasopressin, directed against the V1 and V2 subtypes of the peripheral vasopressin receptor, suggests that the central receptor responsible for the antipyretic effect of vasopressin may resemble the V1 subtype. Recent experiments using electrophysiological techniques have demonstrated the existence of thermoresponsive units in the ventral septal area whose activity may be altered by vasopressin which is possibly derived from the paraventricular nucleus and bed nucleus of the stria terminalis. Electrical stimulation of one of these cell groups in the paraventricular nucleus can reduce the fever evoked by systemic administration of bacterial pyrogen in the rabbit. Collectively, these data strongly support the hypothesis that a system of endogenous antipyresis involving vasopressin exists in the brain. There also may exist another antipyretic system in the brain involving α-melanotropin. This peptide is antipyretic when injected into the dorsal septum and concentrations of α-melanotropin are altered in this area of the brain during fever. Further, passive immunoneutralization using antiserum specific to α-melanotropin results in prolonged fever. A possible connection between the two systems has not yet been investigated. However, in future studies the mechanisms and significance of such a system will be investigated further.