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In this paper, selected historical aspects of thermoregulation and fever are presented as background to the application of molecular biology to thermoregulation. Temperature-sensing mechanisms, coordination of thermal information, thermoregulatory circuitry, efferent responses to thermal stimuli, set point mechanisms, and some of the mechanisms and consequences of fever and hyperthermia are highlighted. Neurotransmitters used in thermoregulatory circuits are also discussed. An attempt is made to include information from comparative physiological sources. Possible future avenues of research in the light of recent new technologies are also presented.

Since submandibular glands participate in the regulation of cardiovascular and immunological responses to bacterial endotoxin, we examined their role as modulators of endotoxin-induced fever. Core body temperatures were measured by telemetry in rats that had either a sham operation or a sialadenectomy 1 week previously and that were maintained at 23-24 degrees C. The sialadenectomized rats showed a circadian variation in body temperature similar to sham-operated rats, although their daytime body temperature was 0.24 +/- 0.01 degree C lower. The fever elicited by intraperitoneal injection of Escherichia coli endotoxin was biphasic, with an initial phase occurring between 2 and 3 h, and a broader second phase peaking between 4 and 8 h after endotoxin injection. The initial fever was similar in the two groups of rats, but the second phase of fever was significantly higher by 0.28 +/- 0.09 and 0.26 +/- 0.07 degree C in sialadenectomized rats receiving 50 or 150 micrograms/kg of endotoxin, respectively. Intravenous treatment with a novel peptide, submandibular gland peptide-T (SGP-T; 100 micrograms/kg), 30 min before endotoxin injection did not affect the early fever response, but significantly suppressed by 0.37 +/- 0.10 degrees C the late-phase fever provoked by 150 micrograms/kg of endotoxin. These results suggest that the submandibular glands modulate thermogenic responses to inflammatory stimuli possibly through the endocrine release of hormones, such as SGP-T.

The effects of the removal of the submandibular glands (sialadenectomy) on the fever induced by bacterial lipopolysaccharide (LPS) were examined. Thermally sensitive radiotransmitters were implanted into the abdomens of adult male Sprague-Dawley rats that experienced at this time either a sham operation or a sialadenectomy, and one week later body temperatures were recorded by telemetry in these rats when conscious. The initial fever (up to 180 min following LPS) response, following the intraperitoneal injection of 150 micrograms/kg E. coli LPS, was similar in the two groups of rats, but the second phase of the fever (240 to 420 min post-LPS) was modestly, but significantly higher (mean = 0.26 degree C) in sialadenectomized rats. A submandibular gland peptide (compound T; 100 micrograms/kg), given one-half hour before the LPS, did not affect the early fever, but suppressed the late-phase fever by 0.37 degree C (mean). The submandibular glands, which form an integral part of the neuroendocrine mechanisms responsible for attenuating the responses of the immune system to inflammatory stimuli, also appear to modulate thermogenic responses to these stimuli.

In the study of mechanisms of thermoregulation conscious animals are used and in most cases the conscious animal is the preferred choice. In some investigations however an anesthetized animal may be the model necessary for the practical purposes of the experimental design. We have developed, tested, and used an urethane anesthetized animal as a model in thermoregulatory investigations. Experiments have been completed in which we have shown that the adult male rat when anesthetized to a surgical level with urethane (1.5 gm/kg) cannot maintain its body temperature and becomes "poikilothermic-like". By providing a steady level of heat to the animal, body temperature can be stabilized for long periods of time at any basal level. This unique feature is not possible in conscious animals. Although apparently poikilothermic, these anesthetized animals respond with a dose-dependent fever to pyrogenic agents such as bacterial pyrogen, interleukin, and prostaglandin. Accompanying these fevers are physiological changes characteristic of fever including increases in arterial and central venous blood pressure, heart rate, oxygen consumption and shivering all of which are similar to the changes which occur in conscious animals. We have used this model for investigations on intracranial pressure, fever suppression and enhancement, application and recovery (for assay) of neuro-transmitters to and from specific brain loci, microdialysis, osmotic stimulation, and electrophysiological stimulation and recording.

Given that relatively little is known regarding the central control of brown adipose tissue (BAT)-mediated thermogenesis the present study assessed whether the direct pharmacological stimulation of beta- or alpha-adrenergic receptors located on the brown adipocytes would result in a typical thermogenic response following electrolytic lesions to the nucleus tractus solitarius (NTS). Bilateral electrolytic lesions to the NTS in the rat effectively disrupted the baroreceptor reflex arc. It was observed that the metabolic and temperature responses to either norepinephrine (1, 5, or 25 micrograms/kg/min) or to the beta-agonist isoproterenol (0.5 micrograms/kg/min) were significantly attenuated in the NTS-lesioned rats relative to the control animals with an intact baroreflex. Conversely, the cardiovascular effects of norepinephrine or of the alpha-agonist phenylephrine (10 micrograms/kg/min) were enhanced in the NTS-lesioned animals. The results suggest that the functional capacity of the brown adipocytes was reduced following NTS lesions and points to an alteration in the ability of beta-receptors to respond to pharmacological stimulation with a typical thermogenic response.

1. Pregnant New Zealand white rabbits were kept from 14 days pre-partum at an environmental temperature of 33 degrees C, and their offspring were reared at this temperature. 2. In response to a 4 hr cold exposure, animals (aged 90-180 days) raised in this way showed significant drops in colonic temperature (-2.7 +/- 0.5 degrees C) while control animals reared at 20 degrees C did not (+0.05 +/- 0.1 degrees C). 3. A reduced, monophasic endotoxin fever was observed in animals reared at 33 degrees C, while a normal biphasic fever was seen in rabbits originally reared at 20 degrees C and subsequently acclimated to 33 degrees C. 4. A greatly reduced temperature response to intravenous infusion of noradrenaline was also found in animals raised at 33 degrees C. 5. It is proposed that thermal afferent input during early life may play an important role in the development of the thermoregulatory system.

A central nervous system pathway appears to exist that can suppress fevers in near-term females and their newborn, as indicated by sheep and guinea pig experiments. This same fever-modulating pathway may control febrile rises in body temperature under normal circumstances. Arginine vasopressin (AVP) may function as a neurotransmitter in this pathway, and evidence for such a role is presented. The significance of a system that negatively modulates fever is discussed from the point of view of the near-term female and newborn, and from the point of view of the normal control of fever.

When pyrogenic substances are injected intravenously into experimental animals, a sequence of events is set in motion which involves the hypothalamus and perhaps other portions of the diencephalon to produce a febrile response. We now present evidence that the brain produces its own endogenous antipyretic which may serve as a means of controlling the extent of the fever. When arginine vasopressin is perfused through the lateral septal area of the hypothalamus of the sheep, fever is suppressed. Vasopressin alone does not lower normal body temperature when perfused through this region of the brain. In addition, evidence is provided to indicate that vasopressin is released within the lateral septal area during the febrile response. It is concluded that, in fever, arginine vasopressin may be released in the lateral septal area of the brain and serve as an endogenous antipyretic. Results indicate that, following an initial application of vasopressin into the brain itself, a subsequent similar administration of vasopressin produces seizure-like activity. Therefore, it is suggested that this release of arginine vasopressin may contribute to the production of febrile convulsion.

The febrile response of the New Zealand White rabbit in animals less than 1 yr old was compared with that in 3-yr-old animals. A reduced febrile response to both endotoxin and live bacteria injected intravenously was observed in the older group of animals. Peripheral vasoconstriction was observed, suggesting the drive to increase body temperature remained. Plasma catecholamines increased significantly in both groups of animals during fever. However, significantly greater increases in plasma epinephrine were observed in the older animals. A significant deficit in catecholamine-induced thermogenesis was observed in the older group of rabbits. This deficit alone does not explain the reduced febrile response, as beta-adrenergic blockade does not suppress the febrile response of young animals. Thus it is suggested that the primary deficit resulting in a reduced febrile response in the 3-yr-old rabbits is due to other age-related changes in the thermoregulatory system.

The neural elements of the rostral diencephalon in the mammal have been implicated in the regulation of body temperature. Moreover, it may be the neural elements within this region of the brain which activate the febrile mechanisms in response to pyrogen. Is it possible that the neuropeptides located within this area of the brain serve as neurochemical intermediaries involved in temperature regulation, fever, and (or) antipyresis? Central administration of several neuropeptides can elicit marked changes in the core temperature of an animal. Although most of these purative neuroregulators exert only a very minor influence on thermoregulation, a small number of the neuropeptides have been shown to have a profound effect on the system controlling this basic vegetative function. One of these peptides, arginine vasopressin (AVP) may play a role as an endogenous antipyretic. The neuroanatomical localization of this peptide, as well as its axonal projections, are consistent with such a role for this neurohypophyseal peptide in the mediation of antipyresis. In addition, current evidence suggests that AVP does function as a neurotransmitter. Examination of the febrile response to pyrogen in both the periparturient animal and the neonate indicates that an elevation in plasma levels of AVP is closely correlated with the diminution in the febrile response. Also, when AVP is perfused into punctate regions of the brain, a pyrogen-induced fever may be markedly suppressed AVP appears to act primarily within the septal area, 2- to 3-mm rostral to the anterior commissure. During the development of fever, the release of AVP is altered within these same loci. As body temperature decreases during the febrile state, there is a concomitant increase in the amount of AVP released into the extracellular fluid of these septal sites. Very recent findings suggest that AVP may have additional central neurochemical functions. For example, this peptide may be involved in the etiology of some forms of convulsive disorders. The precise manner in which body temperature is regulated by the central nervous system normally and during fever is not well understood.(ABSTRACT TRUNCATED AT 400 WORDS)

The experiments reported in this study were designed to investigate the influence of the early thermal environment on the functional properties of certain putative thermoregulatory neurotransmitters within the hypothalamus of the Sprague-Dawley rat. The effects on body temperature of serotonin, dopamine, carbachol, PGE2 and endotoxin when microinjected into the anterior hypothalamic/preoptic region of the brain have been examined in warm-reared, control and warm-acclimated animals. Serotonin and PGE2 are shown to have different effects on body temperature in warm-reared as compared to warm-acclimated and control animals. The thermoregulatory effects of intrahypothalamic dopamine are shown to be changed by the normal acclimation process, while carbachol and endotoxin have similar effects on the body temperature of all 3 groups of animals. These data suggest that the thermal environment may significantly affect the roles which specific neurotransmitters play in the control of body temperature.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnant and nonpregnant female rabbits were placed in hot (33 degrees C) and cold (3 degrees C) environments and their core temperatures measured. Pregnant rabbits during the 3 days before giving birth were less able to maintain normal body temperatures in thermally adverse environments than were nonpregnant rabbits. This alteration in thermoregulatory ability may permit an environmental temperature change that is not dangerous to nonpregnant rabbits to be potentially harmful or lethal to both mother and offspring.

1. Respiratory frequency, shivering, ear skin temperatures and rectal temperatures were observed following intraventricular injections of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and saline (NaCl) into new-born lambs exposed to ambient temperatures of 4, 21, or 30 degrees C. 2. Intraventricular NA caused respiratory rate to decrease and body temperature to increase in the 30 degrees C environment. At 21 degrees C, it increased ear skin temperature but did not significantly affect rectal temperature. At 4 degrees C, NA decreased shivering and rectal temperature fell. 3. 5-HT elevated respiratory rate in the 30 degrees C environment and increased ear skin temperature in the 21 and 4 degrees C environments. In the 4 degrees C environment rectal temperature decreased. 4. In general, the change in rectal temperature was related to the dosage of drug administered. Control injections of NaCl had no significant effect on any of the variables measured. 5. The monoaminergic pathways involved in thermoregulation in the new-born lamb appear to be organized in a manner similar to that of the adult sheep and are functional at birth.

Sprague-Dawley rats were raised in an environmentally controlled room at 33 degrees C. Thermoregulatory responses of animals reared in this way were compared with those of control and warm-acclimated rats. Warm-reared animals demonstrated a significantly greater fall in colonic temperature during cold exposure when compared with both warm-acclimated (p less than 0.01) and control (p less than 0.001) animals. Warm-reared animals also show a modified response to central infusion of noradrenaline; they produce a hyperthermia in contrast with the hypothermia observed in control and warm-acclimated rats. These results suggest that the early thermal environment may modify the development of temperature regulation in the Sprague-Dawley rat in a way different from the normal acclimation process.

Adult male Wistar rats were anesthetized with urethan (1.5 g/kg). They were unable to maintain body temperature (Tb) in a warm (32 degrees C) or cool (9 degrees C) environment or at a laboratory room temperature of 22 degrees C. Tb was allowed to fall to 35.8, 34.5, or 33.3 degrees C, and prostaglandin E1 (PGE1, 400 ng) was delivered into a lateral cerebral ventricle. An immediate feverlike rise in Tb resulted, accompanied by vigorous shivering. Animals were vasoconstricted throughout. When Tb was raised to and maintained at 38.3 or 39.5 degrees C, animals also responded with a fever; however, the magnitude of the fever diminished as the starting Tb increased. In a series of experiments in which Tb was maintained (36.8-37.4 degrees C) by means of a heating pad, PGE1 delivered into a lateral cerebral ventricle or into the anterior hypothalamus caused a dose-dependent change in Tb, which was similar in time of onset, magnitude, and duration to that observed in conscious animals. This fever was accompanied by shivering and increased O2 uptake, heart rate, arterial blood pressure, respiratory rate, and intracranial pressure during the rising phase of the fever, and vasodilation of the paws occurred during defeveresence. Animals were also able to develop a dose-dependent rise in Tb in response to purified human interleukin 1.

1. Noradrenaline (NA) was microinjected into the anterior hypothalamic/preoptic area(AH/POA) of unanaesthetized cats held at ambient temperatures of 10, 22 or 35 degrees C. Loci in which injection of NA caused body temperature changes were also found to be sensitive to the febrile action of PGE1. 2. At all ambient temperatures, NA caused a dose-dependent fall in body temperature. However the mechanisms by which these temperature changes were brought about varied at different ambient temperatures. In cats maintained at the higher ambient temperature, NA activated heat loss mechanisms whereas in the cats maintained in the 10degrees C environment, the major effect of NA injection was an inhibition of heat conservation and heat production mechanisms. 3. We conclude that NA acts in cats not only as an inhibitor of heat conservation and production, but also acts in an excitatory manner on an active heat loss pathway within the AH/POA.

This review compares the physiological changes which accompany infection and fever with the effects of the peptide, arginine vasopressin (AVP). AVP may act as a neuromodulator, a releasing factor, or a hormone to induce responses which are opposite to those homeostatic changes accompanying fever. Since AVP is released into blood and brain during fever, it is hypothesized that AVP contributes to the maintenance of homeostasis in the infected organism.

Thirteen newborn lambs were implanted stereotaxically with an array of 4 guide tubes positioned bilaterally so that their tips lay above various hypothalamic loci. At postnatal ages 50-70 h, rectal temperature was monitored, and bilateral 1 microliter injections were made into the hypothalamus. Prostaglandin E1 (0.2 microgram) and prostaglandin E2 (0.2-2.0 microgram) did not cause fever on any occasion though injections were made into 44 sites throughout the hypothalamus. Nevertheless, lambs that did not develop fever following central injection were often, if sensitized by bacterial pyrogen given earlier able to develop fever after intravenous injection of bacterial pyrogen. Infusion of a bacterial pyrogen (S. abortus equi, 0.2 microgram) into these same sites caused fever only when injections were made into the anterior hypothalamic/preoptic area (AH/POA). Eight lambs were placed in a 10 degrees C environment and noradrenaline was injected. Rectal temperature fell by 0.5-1.4 degrees C after 7 bilateral injections into the AH/POA, but 9 injections into other hypothalamic areas caused little temperature change. When 6 lambs were placed at a temperature of 30 degrees C and noradrenaline was injected, no consistent temperature changes were observed after microinjection into the AH/POA or other parts of the hypothalamus.

Infusion of 15 micrograms/microliters (approximately 120 micrograms/kg/h) of indomethacin within the ventral septal area of the rat brain significantly reduced a centrally induced prostaglandin E1 (PGE1) hyperthermia when compared with infusions of artificial cerebrospinal fluid. A bolus injection of a V1 receptor antagonist, d(CH2)5Try(Me)AVP, (200, 2000, or 20,000 pmol) within the ventral septal area had no effect of body temperature alone but did suppress the PGE1-induced fever. Similar bolus injections of the V1 receptor antagonist within the ventral septal area failed to alter the antipyretic action of indomethacin on the hyperthermia resulting from centrally administered PGE1. Central injections of a V2 receptor antagonist failed to alter either the PGE1-induced fever or the indomethacin-evoked antipyresis. The results suggest that the V1 receptor antagonist may exert non-specific neurodepressant effects which may interfere with the expression or production of PGE1 hyperthermia and may further mask any contribution of arginine vasopressin to the antipyretic effects of indomethacin.

1. Cholinergic synapses in the hypothalamus may transmit information in those thermoregulatory pathways which function to raise body temperature. The effect of atropine, administered intracranially, on the febrile response to intravenous leucocyte pyrogen or intracranial prostaglandin E1 was therefore examined in conscious rabbits. 2. In rabbits exposed to a thermoneutral environment, micro-injections of PGE1, into the anterior hypothalamus, intraventricular injections of PGE1, and intravenous injection so leucocyte pyrogen all caused fever accompanied by vasoconstriction in the ears and reduced respiratory rate. Intraventricular injection of 200 mug atropine during such fevers attenuated their development. This was due to the activation of heat loss mechanisms through vasodilatation in the ears and an increase in the frequency of respiration. This suggests a similarity in the pattern of neuronal activity evoked by PGE1 and leucocyte pyrogen, at least at the site(s) where atropine directly or indirectly exerted its effect and in the efferent pathways from this site. 3. In rabbits exposed to a cold environment, intraventricular injection of PGE1 caused fever through the activation of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shievering and a decrease in O2 consumption so that temperature ceased to rise and returned to normal. 4. During fever, reversal by atropine of the increased heat conservation of rabbits in a neutral environment, and of their increased heat production in a cold environment adds further support to the concept that cholinergic synapses provide an important link in central temperature-rasising pathways.

Prostaglandins appear to be mediators, within the hypothalamus, of heat production and conservation during fever. We have investigated a possible role of prostaglandins in the nonfebrile rabbit during thermoregulation in the cold. Shorn rabbits were placed in an environment of 20 degrees C, and rectal and ear skin temperatures, shivering and respiratory rates were measured. A continuous intravenous infusion of leucocyte pyrogen was given to establish a constant fever of approximately 1 degree C, and after observation of a stable febrile temperature for 90 min, a single injection of 300 mg of sodium salicylate, followed by a 1.5 mg/min infusion was then given. After the salicylate infusion was begun, rectal temperature began to fall, and reached nonfebrile levels within 90 min. Shivering activity ceased, respiratory rates increased, and in two animals, ear skin temperature increased. When these same rabbits were placed in an environment of 10 degrees C, at a time they were not febrile, and an identical amount of salicylate was given, rectal and ear skin temperatures, shivering and respiratory rates did not change. These results indicate that prostagladins do not appear to be involved in heat production and conservation in the nonfebrile rabbit.

The effect of an antipyretic drug administered directly into the preoptic-anterior hypothalamus was measured in order to investigate the role of fever on mortality of bacterially infected mammals. New Zealand white rabbits (Oryctolagus cuniculus) were injected intravenously with Pasteurella multocida and either sodium salicylate or a control solution was infused directly into the preoptic-anterior hypothalamus. Both groups developed fevers, but the fever of the rabbits infused with the antipyretic was reduced by 50% during the initial stage of infection. Hypothalamic sodium salicylate infusions produced a lower average fever than control infusions over an initial 5 hour period of infection, reducing average 5 hour fevers from 1.56 degrees C to 0.72 degrees C. All of the infected rabbits infused with sodium salicylate died whereas only 29% of the infected control rabbits died. Rabbits receiving sodium salicylate alone did not die. The increased mortality could possibly be the result of a fulminating infection caused by rapidly multiplying bacteria during the initial, attenuated phase of the febrile course in the salicylate-treated rabbits.