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Mechanisms and Mediators of Psychological Stress-Induced Rise in Core Temperature

From the Departments of Psychosomatic Medicine (T.O.) and Integrative Physiology (T.O., K.O., T.H.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and the Department of Neurology (T.O., K.O.), Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts.

Address reprint requests to: Takakazu Oka, MD, PhD, Harvard Institutes of Medicine 819, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: toka{at}caregroup.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
OBJECTIVE: Despite numerous case reports on "psychogenic fever," it remains uncertain how psychological stress raises core temperature and whether the rise in core temperature is a real fever or a hyperthermia. This article reviews studies on the psychological stress–induced rise in core temperature (PSRCT) in animals with the aim to facilitate studies on the mechanisms of so-called psychogenic fever in humans.

METHODS: To address this question, we reviewed the mechanisms and mediators of the PSRCT and classic conditioning of the fever response in animals.

RESULTS: The PSRCT is not due to the increased locomotor activity during stress, and the magnitude of the PSRCT is the same in warm and cold environments, indicating that it is a centrally regulated rise in temperature due to an elevated thermoregulatory "set point." The PSRCT caused by conventional psychological stress models, such as open-field stress, is attenuated by cyclooxygenase inhibitors, which block prostaglandin synthesis. On the other hand, the PSRCT elicited by an "anticipatory anxiety stress" is not inhibited by cyclooxygenase inhibitors but by benzodiazepines and serotonin Type 1A receptor agonists. The febrile response can be conditioned to neutral stimuli after paired presentation with unconditioned stimuli such as injection of lipopolysaccharide, a typical pyrogen.

CONCLUSIONS: Most findings indicate that the PSRCT is a fever, a rise in the thermoregulatory set point. The PSRCT may occur through prostaglandin E₂–dependent mechanisms and prostaglandin E₂–independent, 5-HT–mediated mechanisms. The febrile response can be conditioned. Thus, these mechanisms might be involved in psychogenic fever in humans.

Key Words: psychogenic fever • emotional hyperthermia • stress-induced hyperthermia • stress • fever • fever of unknown origin.

Abbreviations: CRF = corticotropin-releasing factor; GABA = -aminobutyric acid; 5-HT = serotonin; ICV = intracerebroventricular; IL-1 = interleukin-1; IL-6 = interleukin-6; IFN = interferon; IM = intramuscular; IP = intraperitoneal; IV = intravenous; LPS = lipopolysaccharide; MIP-1 = macrophage inflammatory protein-1; -MSH = -melanocyte-stimulating hormone; PGE₂ = prostaglandin E₂; PO = per os (by mouth); POA = preoptic area of the hypothalamus; PSRCT = psychological stress–induced rise in core temperature; SC = subcutaneous; Tco = core temperature; TNF = tumor necrosis factor.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
Does psychological stress cause fever? Human core temperature is tightly regulated around 37°C, although it varies diurnally, decreasing to a minimum during the night (1). Recent studies have revealed that not only circadian rhythms but also psychological stress can affect Tco. For example, Tco is reported to be higher after watching films (2) and just before boxing contests (3) or examinations (4–7). In most cases, however, the changes are <1°C, and the raised core temperature rarely exceeds the upper limit of normal body temperature (37–37.7°C) (for review of normal temperature, see Ref. 1). For example, Marazziti et al. (6) observed that mean axillary temperature of healthy adults before an examination was 0.6°C higher than that measured when the subjects were in a relaxed condition several weeks later. In addition, there have been numerous case reports on elevated core temperature possibly caused by psychological stress, which is generally called "psychogenic fever" (8–28). In patients with "psychogenic fever," Tco is often elevated to 38°C and may remain high for weeks to even years (15, 20, 24). In some cases, psychological stress raised the Tco up to 39°C, eg, during arguments with a sister (8), during a visit with a strict mother (22), or in a situation that aroused anger (23). In other cases, strong suppression of negative emotions, such as aggression, is suggested to cause elevated temperature (16, 17). However, it remains uncertain how psychological stress or suppressed emotional expression raises Tco in these patients. Furthermore, it still is in dispute whether the raised Tco in patients with psychogenic fever is a real fever, ie, a centrally regulated rise in body temperature (25).

The phenomenon of psychological stress–induced fever is also observed in laboratory animals. Recent animal studies have shown that several mediators are involved in the PSRCT. This article, therefore, reviews the mechanisms and mediators of PSRCT in animals with the aim of understanding psychogenic fever in humans.

	WHAT IS FEVER?

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
Fever is a centrally regulated rise in core temperature. Fever is often described as being due to a raised "set-point temperature," toward which the thermoregulatory system works to raise Tco (29). To achieve this set point, the brain orchestrates changes in autonomic, neuroendocrine, and behavioral thermoregulatory responses by increasing heat-production responses (shivering, nonshivering thermogenesis, and heat-seeking behavior) and decreasing heat-loss responses (sweating, cutaneous vasodilatation, and cool-seeking behavior). When Tco reaches the set point, these imbalanced patterns of thermoregulatory responses disappear, and the Tco is now regulated at the new high set point. Namely, fever is an "active hyperthermia" that is achieved by command signals from the brain.

In contrast, a "passive, forced hyperthermia" is a rise in Tco above the set-point temperature. This results from an increased heat load that may be due to inadequate heat dissipation in a warm environment or overproduction of body heat by general physical activity and malignant hyperthermia (29–31). In a passive and forced hyperthermia, the thermoregulatory system attempts to bring core temperature down to the normal temperature. Therefore, a passive, forced hyperthermia is expected to be accompanied by cutaneous vasodilatation, increased evaporative heat-loss responses (eg, panting and wallowing), and cool-seeking behavior. These response patterns are opposite those seen in the organism during the rising phase of fever as described above.

Mechanism of Fever Induction: An Overview
Fever is initiated by the appearance of exogenous pyrogens within the body, eg, invading microorganisms that act on immune cells, particularly mononuclear phagocytes, and thereby induce the production of endogenous pyrogen. Endogenous pyrogen is now known as a group of proinflammatory cytokines such as IL-1, IL-1ß, IL-6, TNF-, IFN-, and MIP-1 (32). These cytokines signal the brain by (1) active transport of cytokines into the brain (2), a blood cytokines-to-brain signal transduction at the circumventricular organs (eg, the organum vasculosum laminae terminalis) (3), the production of brain-permeable paracrine substances at endothelial cells in the cerebral microvessels (eg, PGE₂ synthesis), and (4) stimulation of somatic and visceral (vagal) afferent nerves (33–35). Furthermore, during systemic infection, these cytokines are also produced in the brain, mostly by glial cells, and such brain-derived cytokines also play a role in the development of fever. The signals from these cytokines in both the periphery and the brain ultimately alter the activity of thermosensitive neurons in the POA, a critical thermoregulatory center. In this process, PGE₂ is believed to act as a principal, final mediator of fever (34).

On the other hand, fever is also negatively controlled by endogenous cryogens such as IL-1 receptor antagonist, -MSH, and glucocorticoids, so that the febrile temperature does not exceed the set-point temperature. TNF- also acts as an endogenous cryogen under certain circumstances (32).

Thermosensitive Neurons Respond to Emotional Stimuli
Thermosensitive neurons in the POA are assumed to be essential central regulators of body temperature (34, 36). Thermosensitive neurons consist of two types of neurons, cold-sensitive and warm-sensitive neurons. Electrophysiological studies in vivo and in vitro have revealed that both systemic and local applications of endogenous pyrogens increase the firing rate of cold-sensitive neurons and decrease that of warm-sensitive neurons (see Ref. 36 for review). Because the cold-sensitive and warm-sensitive neurons in the POA are thought to mediate activation of heat-production and heat-loss responses, respectively, these neuronal responses may explain the increased heat production and the decreased heat loss during the rising phase of fever. Furthermore, some POA thermosensitive neurons respond to nonthermal homeostatic parameters such as osmolality and blood pressure and may thereby coordinate thermoregulation with osmotic or cardiovascular regulation (36). Interestingly, the activity of a considerable population of POA thermosensitive neurons is affected by nonthermal emotional stimuli in monkeys, eg, watching rewards (foods) or aversive objects (an air puffer or toy snake) (37). This finding may explain changes in thermoregulation by nonthermal emotional and psychological factors if not PSRCT. For instance, in humans sweating rate at the chest and abdomen changes rapidly during mental arithmetic and emotional statements of experimenters (38).

	PSRCT IN LABORATORY ANIMALS

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
In many species, psychological stress results in an acute rise in Tco. For example, handling stress or exposure to novel environments can raise core temperature as much as 2°C in rats (39–43). A similar phenomenon is observed in other species, including mice (44, 45) and rabbits (46, 47). An "emotional" as well as pyrogenic increase in Tco has been observed even in reptiles, in which thermoregulation is achieved only by behavioral means. When lizards are gently handled, they move toward an infrared lamp in the experimental room to elevate their Tco in a way similar to when they are infected with bacteria (48). This suggests that hyperthermic responses to emotional stimuli as well as infectious stimuli have an old phylogenetic origin.

Psychological stress models commonly used in these studies are simple handling, open-field stress (ie, removing an animal from its home cage and placing it in a large open space), cage-change stress (ie, placing an animal in a new cage), cage-exchange stress (ie, exchanging cages between two animals so that animals are exposed to the olfactory and visual stimuli associated with the new environment), and putative "anticipatory anxiety" stress (ie, group-housed animals are removed one by one from their home cage at a fixed time interval, and the body temperature at the time of removal is higher in each successive animal).

	CENTRAL AND PERIPHERAL MEDIATORS OF PSRCT

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
Prostaglandin E₂
Fever during infection is thought to be mediated by prostaglandins (primarily PGE₂) released in the POA (34). Therefore, cyclooxygenase inhibitors, drugs that block prostaglandin synthesis, suppress pyrogen-induced fever. These antipyretics also attenuate the rise in Tco caused by various forms of stress in rats, ie, open-field (40, 49), handling (50), or cage-change (51) stress. Cyclooxygenase inhibitors also attenuate the increase in Tco due to physical restraint in pigs (52, 53). For instance, IP or ICV administration of sodium salicylate (40, 49) and indomethacin (IP) (49) significantly reduced the open-field stress–induced rise in Tco in rats at doses that had no effect on body temperature of nonstressed rats. Similarly, pretreatment with indomethacin (IP) suppressed the cage-change stress–induced rises in Tco and plasma levels of PGE₂ and adrenocorticotropic hormone (51). Furthermore, salicylate (IP) inhibited behavioral fever due to gentle handling in the lizard Callopistes maculatus (48). Velluci and Parrott (53) demonstrated that restraint stress in pigs enhanced expression of c-Fos, a marker of neuronal activation, in the median preoptic nucleus, which is located in the POA, and that indomethacin markedly inhibited its expression. These observations suggest that, like pyrogen-induced fever, a major portion of the PSRCT described above is mediated by PGE₂-induced activation of thermoregulatory neurons in the POA.

The core temperature of rats starts to rise within minutes and reaches a peak within 15 minutes after exposure to open-field stress (40). If the open-field stress–induced rise in Tco is mediated by PGE₂ synthesized in the POA, how does psychological stress stimulate the rapid synthesis of PGE₂? Although the mechanism is not fully understood, it is possible that psychological stress activates noradrenergic neurons in the locus ceruleus (54, 55), the neural signals are conveyed to the POA via the ventral noradrenergic bundle, and release of noradrenaline in the POA stimulates the synthesis of PGE₂ in local neurons and/or astrocytes (34). In support of this hypothesis, stress increases noradrenaline release in the hypothalamus (56), and microdialysis infusion of noradrenaline into the POA rapidly increases local production of PGE₂ in guinea pigs (57), as can be seen with IP injection of LPS in models of bacterial infection (58).

Therefore, a major portion of some types of PSRCT seems to be induced by altered activities of thermosensitive neurons in the POA that are stimulated by locally released PGE₂. This provides further evidence that at least some types of PSRCT are true fever (49, 59).

Interleukin-1
Although IL-1 and IL-1ß have been considered to be principal mediators of fever, their contributions differ depending on the fever model. For instance, they seem to be critical in SC turpentine-induced fever, a local inflammation model, in mice. However, their contributions to IV or IP LPS-induced fever seem to be small in mice and rats (60–62).

The open-field stress–induced rise in Tco and the LPS-induced fever were not blocked by IP pretreatment with antiserum against murine IL-1 at a dose that could block IM murine IL-1–induced fever (63). Similarly, injection of antiserum against IL-1ß failed to affect the stress-induced hyperthermia (64). Therefore, circulating IL-1 and IL-1ß do not seem to be involved in PSRCT. However, possible involvement of neural signals arising from IL-1 produced in peripheral tissues (eg, liver) and brain remains to be determined.

Interleukin-6
Kluger’s group (65, 66) hypothesized that LPS-induced fever is mediated by IL-1ß–induced production of IL-6, which is proposed as a final common mediator in the cytokine cascade for febrogenesis. There is a good correlation in the magnitude and time course between IL-6 levels in plasma and cerebrospinal fluid and the rise in Tco during LPS-induced (IP) fever (32).

Open-field stress in rats (66, 67) and cage-exchange stress in mice (68) also increase plasma levels of IL-6. A positive correlation was found between the IL-6 levels and the rises in Tco in rats during open-field stress. However, LeMay et al. (66) concluded that the magnitude of such a stress-induced rise in plasma IL-6 was not high enough to account for the rise in Tco during this stress. To support this opinion, IP injection of antimurine IL-6 antibody did not attenuate the cage-change stress–induced rise in Tco in mice, although it reduced plasma levels of IL-6 by half before and after the stress (68). Therefore, circulating IL-6 may not be involved in PSRCT. However, it remains possible that IL-6 released in the brain (66) or abdominal tissues, such as liver and gut-associated lymph nodes, mediates PSRCT (69).

Tumor Necrosis Factor
TNF was not detected in either the plasma or the cerebrospinal fluid of rats after a 15-minute exposure to open-field stress. However, IP injection of rats with antiserum against TNF enhanced the PSRCT produced by either open-field stress or cage-exchange (switch) stress (64). It thus seems that TNF acts as an endogenous antipyretic by itself or as an inducer of an antipyresis, limiting the rise in core temperature induced by psychological stress (64) in the same way it does in LPS fever (70).

Opioid Peptides
In addition to PGE₂, endogenous opioid peptides and/or central opioid receptor mechanisms are also assumed to mediate fever (71–74). For instance, direct application of IFN- to brain tissue slices alters the firing rate of POA thermosensitive neurons in a naloxone-reversible way (naloxone is an opioid receptor antagonist) (75). Thus, IFN-–induced (ICV) fever is suggested to be mediated by two different mechanisms in rats, its binding to opioid receptors of POA neurons and local production of prostaglandins (76, 77).

Available data are controversial as to whether opioid peptides and/or receptors are involved in PSRCT. Several investigators have demonstrated that naloxone inhibits the rises in Tco caused by handling and open-field stress (39, 42, 78–80). Pituitary secretion of ß-endorphin may play an important role in the handling-induced rise in Tco because its PSRCT was attenuated by hypophysectomy (39). Because the rise in Tco due to handling stress was blocked by naltrexone, an opioid receptor antagonist, injected into the POA, it was suggested that ß-endorphin released from the pituitary gland enters the brain and acts on opioid receptors in the POA to raise Tco (80). It is also possible that opioid peptides are released in the brain during psychological stress and produce the PSRCT. Conversely, other studies have shown the failure of naloxone to block novelty or open-field stress–induced rise in Tco in rats (40, 81), although it reduced basal Tco (81). These authors therefore concluded that endogenous opioids would not be significantly involved in PSRCT.

Corticotropin-Releasing Factor
CRF is released mainly from neurons of the paraventricular nucleus of the hypothalamus during stress, and it may play an important role in stress-induced physiological responses. CRF in the paraventricular nucleus of the hypothalamus may activate the sympathetic nerves innervating the brown adipose tissue, thereby contributing to thermogenesis during cold exposure, excessive food intake, and inflammatory and noninflammatory stress (82, 83). Cage-change stress–induced rise in Tco as well as hypertension and tachycardia were attenuated by ICV injection of -helical CRF_9–41, a CRF antagonist, at doses that had no effect on these physiological parameters in unstressed rats (84, 85). Therefore, central CRF seems to be an important mediator of the PSRCT.

Glucocorticoids
Glucocorticoids exert an inhibitory feedback action on PSRCT (open-field stress) as well as LPS-induced fever in rats. Both adrenalectomy and administration of a Type II glucocorticoid receptor antagonist RU-38486 (PO and ICV) lead to enhancement of PSRCT (open-field stress) and LPS-induced fever in rats (86–88). However, microinjection of RU-38486 in the anterior hypothalamus augmented LPS fever but not PSRCT. On the other hand, PSRCT was enhanced by transection of the fornix (87). Because the hippocampus has a high density of Type II glucocorticoid receptors (89), the neural connections between the hippocampus and the hypothalamus, the hippocampus itself, and/or brain sites that send axons to the hippocampus, may be a primary target of glucocorticoids in modulating the PSRCT.

Noradrenaline
It is well known that stress augments the release of noradrenaline in the hypothalamus (56). A stress-induced rise in Tco may be due to release of noradrenaline in the POA because intra-POA administration of noradrenaline increases Tco in rats and guinea pigs (90, 91). Furthermore, local application of noradrenaline facilitates the activities of cold-sensitive neurons and inhibits those of warm-sensitive neurons in the POA in rats and rabbits (92, 93), which would provide thermoregulatory effects appropriate for fever.

ICV injection of ß-adrenergic receptor antagonists inhibited the increase in Tco caused by exposure to open-field stress (67) and immersion in shallow water, which is supposed to be a psychological stress model, in rats (94). On the other hand, nadolol (IP), a nonspecific ß-receptor blocker that cannot cross the blood-brain barrier, did not affect the open-field stress–induced rise in Tco (67). Therefore, ß-adrenoreceptors in the central nervous system, most probably in the POA, may be involved in PSRCT in rats. Because the rise in Tco after intra-POA injection of noradrenaline is not attenuated by cyclooxygenase inhibitors, open-field stress–induced rise in Tco may be caused by direct action of noradrenaline on the POA thermosensitive neurons as well as the noradrenaline-induced, PGE₂-mediated mechanism (see Prostaglandin E₂).

Serotonin
The role of 5-HT in thermoregulation is complicated. Earlier studies demonstrated that direct application of 5-HT increased the firing rate of warm-sensitive neurons and decreased that of cold-sensitive neurons in rats and rabbits (77, 92). These neuronal responses are consistent with the hypothermic effect of ICV administration of 5-HT (95) but not with a rise in Tco by intra-POA administration of 5-HT (96). More detailed studies demonstrated that 5-HT raised Tco when it was injected into the rostral POA and reduced it when given into the caudal POA in cats (97). Recent pharmacological studies have revealed that the hypothermic effect is mediated by 5-HT_1A receptors and that the hyperthermic effect is mediated by an activation of 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors in rats and mice (98–101).

The possible involvement of 5-HT in the PSRCT has been investigated using a putative "anticipatory anxiety" stress model, ie, group-housed mice are removed one by one from their home cage every minute, and the rectal temperature at the time of removal is higher in each successive animal such that the mouse removed last has a rectal temperature about 1.5°C higher than the one removed first. This stress-induced rise in Tco is attenuated by pretreatment with anxiolytic drugs such as 5-HT_1A receptor agonists (flesinoxan and buspirone) (45, 102, 103) and benzodiazepines (diazepam, alprazolam, and chlordiazepoxide) (44, 102, 103), but not by 5-HT_2A/C receptor antagonists (ketanserin, LY53857) (102, 104–106).

One of the remarkable properties of this type of PSRCT is that it is independent of prostaglandins and opioids, as evidenced by the failure of cyclooxygenase inhibitors and naloxone to affect it (102, 104). Furthermore, this anticipatory anxiety stress–induced rise in Tco is attenuated by prazosin, an ₁-adrenoceptor antagonist (102, 104), but not by chlorpromazine, which exerts a hypothermic effect by blocking peripheral ₁-adrenoceptors (104), suggesting its central action. These data suggest that activation of ₁-adrenoceptors and inhibition of 5-HT_1A receptors in the central nervous system are involved in anticipatory anxiety stress–induced rise in Tco in mice.

-Aminobutyric Acid
Anxiolytic drugs such as benzodiazepines are reported to inhibit anticipatory anxiety stress–induced rise in Tco in mice (44). -Acetylenic GABA, an inhibitor of GABA catabolism, also blocked the rise in Tco caused by exposure to an unfamiliar environment in rats (81). Therefore, the GABA/benzodiazepine system may exert an inhibitory effect on the PSRCT.

Dopamine
Dopamine can decrease Tco by its facilitatory actions on warm-sensitive neurons and inhibitory actions on cold-sensitive neurons in the POA in rats (107). However, neither dopamine receptor antagonists (sulpiride, haloperidol, and pinozide) nor a dopamine receptor agonist (apomorphine) altered the anticipatory anxiety stress–induced rise in Tco (102, 104). Therefore, dopamine may not be involved in the anticipatory anxiety stress–induced rise in Tco. The effects of dopamine on the other types of PSRCT have not been examined.

Sympathetic Nervous System
Restraint stress increases thermogenesis of brown adipose tissue through stimulation of ß₃ receptors on brown adipose tissue by sympathetic nerves (108). However, IP injection of nadolol, a peripheral ß-adrenoreceptor blocker, did not affect the increase in Tco and metabolic rate caused by open-field stress and cage-change stress (67, 94). In contrast, phentolamine (IP), an -adrenoreceptor blocker, attenuated the cage-change stress–induced rise in Tco without affecting the increase in metabolic rate during stress (94). These findings suggest that peripheral -adrenoreceptor–mediated vasoconstriction of skin blood vessels, not ß-adrenoreceptor–mediated nonshivering thermogenesis, plays an important role in PSRCT in rats.

The possible mediators and modulators of PSRCT are summarized in Table 1.

	CLASSIC CONDITIONING OF THERMOREGULATORY RESPONSES

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

	IS PSRCT A FEVER OR A PASSIVE HYPERTHERMIA?

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 
Some Kinds of PSRCT Are Fever
Is the PSRCT a true fever or a passive, forced hyperthermia? There are several reasons to believe that some kinds of PSRCT (handling, exposure to an open field, cage change, cage exchange, or restraint) are fever. First, cage-exchange stress–induced rise in Tco is not caused by increased physical activity. The rise in Tco of rats after cage exchange during the day correlated poorly with the increase in physical activity, and that at night correlated negatively (64). Second, PSRCT in the above models, like pyrogen fever, exhibits characteristics of a rise in the thermoregulatory set point. Specifically, the open-field and cage-exchange stress–induced rise in Tco in rats, like pyrogen fever, is not affected by ambient temperature (59, 122). If this were a passive hyperthermia, the rise in Tco would be greater in a warm environment than in a cold environment. In addition, the rising phase of PSRCT is accompanied by vasoconstriction in the tail skin, an appropriate thermoregulatory response for heat conservation (59). If PSRCT were due to a passive hyperthermia, it would be accompanied by vasodilatation. Furthermore, after gentle handling, lizards move toward an infrared lamp to raise their Tco in a way similar to when they are infected with bacteria (48). This clearly shows that they have "motivation" to raise their Tco. The mammals would seek heat and avoid cold stimuli during the rising phase of PSRCT and pyrogen fever (123, 124), although this has not yet been studied. Third, PSRCT and pyrogen fever share, at least partially, common mediators. The major portion of the rise in Tco caused by stresses (open field, cage change, cage exchange, and restraint), like pyrogen fever, is dependent on the actions of PGE₂ in the POA (40, 49, 51). Furthermore, antiserum against TNF increases PSRCT in the same way it does in LPS fever (64, 70).

Challenging Findings Against the View That PSRCT Is a Fever
Some observations, however, challenge the view described above. For instance, several findings show the dissociation between LPS fever and PSRCT. First, in the LPS-tolerant rat, further administration of LPS does not produce fever, but open-field stress can still produce a rise in Tco (125). Second, as stated above (see Glucocorticoids), the brain sites where glucocorticoids act to suppress the rise in Tco differ between LPS-induced fever and open-field stress–induced rise in Tco (87, 88). These findings suggest that PSRCT, at least after exposure to an open field, is not mediated by LPS or LPS-induced prostaglandins. However, it remains possible that it is mediated by prostaglandins, which may be induced by cytokines and noradrenaline acting in the brain during psychological stress.

Another report showed that rise in Tco induced by handling of rats was higher in a cold environment (8°C) than in a warm environment (31°C) (126). This should not occur if the change in Tco is due to a rise in the set point. The report contradicts other observations that PSRCT caused by handling and open-field exposure were not affected by ambient temperature (59, 122). It may be that rats in a cold environment had already activated mechanisms for heat production and suppressed those for heat dissipation; thus, they could readily raise Tco in response to handling. Another possibility is that rats tend to be more alert in a cold environment, as evidenced by electroencephalographic arousal patterns, and the rise in Tco could be related to increased wakefulness. If the latter case is applicable, some portion of PSRCT might not be due to the rise in the thermoregulatory set point. Nevertheless, the majority of findings support the view that a major portion of the PSRCT described above is a centrally regulated fever.

Anticipatory Anxiety–Induced Rise in Core Temperature
An intriguing finding is that the rise in Tco caused by anticipatory anxiety stress is not affected by cyclooxygenase inhibitors or naloxone, but it is attenuated by benzodiazepines and 5-HT_1A receptor agonists (102). The fact that the rise in core temperature is not affected by cyclooxygenase inhibition does not necessarily mean that it is not a fever. For example, proinflammatory cytokines such as MIP-1 produce fever through prostaglandin-independent mechanisms (127). Therefore, the question still remains whether anticipatory anxiety stress–induced rise in Tco is a result of a rise in set-point temperature. As stated (see Serotonin), 5-HT alters the activity of POA thermosensitive neurons and thereby induces hypothermia in rats and rabbits (77, 92). Further studies are required to determine whether anticipatory anxiety–induced hyperthermia is a fever.

It should be noted that cyclooxygenase inhibitors cannot completely abolish the PSRCT induced by open-field stress (40) or cage-change stress (51). This suggests the involvement of mediators other than prostaglandins in the PSRCT and/or that the PSRCT includes nonfebrile components, such as changes in heat production and cutaneous vasomotor activities, that are associated with stress response itself. It is possible that fever and hyperthermia coexist (59).

Does PSRCT Have an Adaptive Value Like Fever?
Fever during infection is considered to have beneficial effects for infected hosts, because blocking the production of fever in infected animals increases mortality (32). Fever (about 39–41°C) exerts adverse effects on the growth of invading microorganisms and facilitatory effects on host T-cell–mediated immunity, thereby decreasing the mortality of infected hosts (128, 129). The PSRCT would be an adaptive response that the organisms, warned by stress signals, prepare for the possible "fight or flight" situation, which is potentially accompanied by body injury. For example, a lizard living alone in a cage starts to seek infrared heat when another lizard is introduced into the cage and stops this heat-seeking behavior when the invading lizard is removed (130). This change in thermoregulatory behavior suggests that the first lizard maintains a higher Tco so that it has a better chance to defeat the invader (130). The physiological significance of PSRCT, however, still remains to be investigated.

	PERSPECTIVES FROM ANIMAL MODELS

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Two Possible Mechanisms of PSRCT
Based on the findings in the laboratory animals, we can postulate at least two different mechanisms of PSRCT: 1) a PGE₂-dependent mechanism and 2) a PGE₂-independent, 5-HT–mediated mechanism. In both mechanisms, noradrenaline may be involved, but quite differently (Table 2). In the first model, psychological stress may activate the noradrenaline system (particularly the locus ceruleus-ventral noradrenergic bundle-hypothalamus pathway) to stimulate the synthesis of PGE₂ in the POA. Then, PGE₂ acts on thermosensitive neurons to orchestrate the febrile response. In the second model, which is applicable to anticipatory anxiety stress, the central noradrenaline system is activated in a yet unknown manner, and central 5-HT_1A receptor–mediated actions are suppressed, thereby raising the Tco independently of PGE₂ synthesis, although it is unknown how anxiety leads to the inhibition of 5-HT_1A receptors and the eventual rise in Tco.

Animal studies suggest that the principal mediators and modulators of psychogenic fever are classic neurotransmitters (noradrenaline and 5-HT), GABA, neuropeptides (eg, CRF), and prostaglandins. Further studies are required to understand how they interact for the development of PSRCT in laboratory animals and humans.

Received for publication January 13, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION WHAT IS FEVER? PSRCT IN LABORATORY ANIMALS CENTRAL AND PERIPHERAL MEDIATORS... CLASSIC CONDITIONING OF... IS PSRCT A FEVER... PERSPECTIVES FROM ANIMAL MODELS REFERENCES

 

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