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J Appl Physiol 92: 1717–1724, 2002;
10.1152/japplphysiol.01051.2001.
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Molecular Biology of Thermoregulation
Some historical perspectives on thermoregulation
K. E. COOPER
Department of Physiology and Biophysics, Faculty of Medicine,
University of Calgary, Calgary, Alberta, Canada T2N 4N1
temperature; hypothalamus; temperature sensing; fever
is to outline some aspects of
thermoregulation, setting them in historical context as
well as making reference to some recent findings made
at the cellular level. It is not intended to be an exhaustive review of all aspects of thermoregulation but to set
the stage for papers on molecular biological studies.
For greater breadth and depth, the reader should see
the following reviews of the mechanisms of body temperature regulation and their disorders: Kuno (47),
Kluger (44), Satinoff (65), Hensel (36), Hellon and
Townsend (34), Stitt (70), Moltz (55), Cooper (15), Zeisberger (76), Blatteis et al. (8), and Gisolfi and Mora
(28).
Development of thermometers led to the scientific,
quantitative study of thermoregulation. Mercury-inglass thermometers were available to James Currie
(18) in 1798, who used them as diagnostic and prognostic tools in his clinical studies, in his studies of
fever, and in his experiments on cold water immersion.
The wide use of thermometry in clinical practice came
after the publication of Wunderlich’s (74) Manual of
Medical Thermometry in 1868. Wunderlich attempted
to define the character of temperature changes associated with specific disease processes. He described the
THE INTENTION OF THIS PAPER
Address for reprint requests and other correspondence: K. E.
Cooper, Dept. of Physiology and Biophysics, Faculty of Medicine,
3330 Hospital Dr. NW, Univ. of Calgary, Calgary, AB, Canada T2N
4N1 (E-mail: [email protected]).
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body temperature ranges of mammals, birds, reptiles,
insects, and fish and the diurnal temperature variations and the effects of exercise on body temperature.
The exploitation of thermoelectricity by Becquerel and
Breschet (4) in 1835 enabled Lefèvre (48) to use thermocouples to measure the thermal topography of the
body. Lefèvre (48) also described whole animal and
human calorimetry for determining metabolic rates, a
technique used later by Dubois (23) to study fever and
by Benzinger (6) as a partition calorimeter to investigate the central control of core temperature. Analytical
equipment and neurophysiological and physicochemical techniques to explore the mechanisms of thermoregulation in the whole animal and at the molecular
level have since multiplied almost exponentially. With
the use of these new methods, researchers are now at
the threshold of a much deeper understanding of the
basic mechanisms of thermoregulation.
Knowledge of the mechanisms of thermoregulation
has progressed from the crude localization of areas
within the central nervous system involved in thermoregulation to fuller, but still incomplete, mapping of
areas in the neural circuitry necessary to receive and
process thermal inputs. Regulatory effector mechanisms have also been explored. Currie (18) and Liebermeister (49) knew that body temperature is a regulated
entity. Ott (59) made brain stem sections and concluded that there are centers in the region of the
corpora striata that affect thermoregulation. Ranson
8750-7587/02 $5.00 Copyright © 2002 the American Physiological Society
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Cooper, K. E. Some historical perspectives on thermoregulation. J Appl
Physiol 92: 1717–1724, 2002; 10.1152/japplphysiol.01051.2001.—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.
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HISTORICAL PERSPECTIVES
J Appl Physiol • VOL
SENSING TEMPERATURE AND
TEMPERATURE CHANGE
The ability of an organism to sense the temperature
of its environment, and the temperatures of its body
components, is fundamental to the control of its body
temperature. There are specialized nerve endings in
vertebrate endotherms and ectotherms that can detect
and respond to both steady temperature and rapid
changes in temperature. Some protozoa were shown to
sense temperature and move to preferred temperature
zones, e.g., Paramecium and Oxytrica (41, 52). The
ability to sense temperature developed very early in
phylogeny; by studying simple unicellular organisms,
researchers can find clues to mechanisms that may
parallel the events of thermal perception in multicellular organisms. Recent studies (40) in Paramecium
have shown that various ion channels are involved in
perception of temperature, such as different calcium
channels responding to heating and cooling. It is possible that a temperature-detecting mechanism could
involve both calcium channels and/or potassium channels shared with a mechanoreceptor (71), but this is yet
to be determined. Discovery of temperature-sensitive
ion channels has led to the study of the events that
their activation brings about within the cell and the
subsequent activation of the cell cilia. A recent study
(56) suggests that prostaglandin I2 may be a thermosensory mediator in Paramecium. In multicellular
organisms having nervous systems, there are many
neurons that exhibit temperature sensitivity. Although many of these form part of thermoregulatory
control systems, the possession of thermosensitivity
does not necessarily imply such a connection. For example, there are thermosensitive neurons in the sensorimotor cortex in the cat that appear not to have a
role in thermoregulation (3). Thermosensitive neurons
involved in thermoregulation respond to thermal stimulation by altering their pattern of spike discharges
(36, 39). One can thus imagine that thermosensitive
neurons behave as unicellular organisms; that is, when
unable to move, they send out signals to be integrated
with those of many other such cells, causing the whole
organism to adjust to the changing thermal environment and preserve its internal thermal topography!
To be classified as a specific (peripheral) temperature receptor, four criteria must be met (35): 1) the
neuron must exhibit a static sensitivity to constant
temperature, 2) the neuron must show a dynamic response to temperature change with a positive coefficient in warm receptors and a negative coefficient in
cold receptors, 3) the neuron must not be excited by
moderate mechanical stimuli, and 4) neuron activity
must occur within the innocuous or nonpainful range of
temperature (35, 36). The pattern of neuron discharge
in response to a change in temperature is both dynamic
and static (see Refs. 35 and 39). The plot of static
neuron discharge frequency against receptor temperature is bell shaped. The warm receptors increase their
firing rate with increasing temperature, and the cold
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(62) and Ranson and Magoun (63) used discrete local
heating and lesioning to locate thermoregulatory structures within the hypothalamus. Details of the anatomic locations of the regulating mechanisms, which
were later, were fully discussed by Bligh (9). Coding of
thermal information that projects to the extremely
important regions within the hypothalamus (which
respond to incoming thermally generated signals) has
been studied. Dodt and Zotterman (21), Hardy (32),
Iggo (39), and Hensel (35) investigated the coding of
peripheral thermal sensation. They analyzed the characteristics of “warm” and “cold” receptor responses to
thermal stimulation. However, the process of translation of neural firing patterns from peripheral temperature receptors into conscious sensations of heat and
cold is still a mystery. One is reminded of a line in an
old hymn: “the mystic harmony linking sense to sound
and sight.”
Our knowledge of the complex circuits within the
hypothalamus subserving thermoregulation has been
greatly advanced by observations made on hypothalamic tissue slices (10). The molecular mechanisms of
transduction of temperature sensing into neural firing
patterns and the molecular events in the postsynaptic
regions of the synapses, which cause sequential neural
stimulation leading to the initiation of vascular smooth
muscle responses or tissue heat production, are now
being unraveled. It is generally accepted that the body
temperature is regulated about a physiologically determined set point. The mechanism by which the set point
is determined is still a mystery.
Studies in comparative physiology have added
breadth to our concepts of thermoregulation. For example, thermoregulation occurs in ectotherms as well
as in endotherms by behavioral means. Ectothermic
animals can shuttle between direct sunlight and shade
to maintain a remarkably steady core temperature
during daylight hours. Some mammals have evolved
the ability to hibernate, allowing them to survive in a
state of torpor over cold winters. Grant’s Golden mole
(Erimetalpa grantii), which lives in the Namib desert,
lets its core temperatures fall over a large range while
maintaining a surprising amount of hunting activity. It
“swims” deeply into cool layers of very fine desert sand
and reduces its body temperature and so lowers oxygen
(and energy) expenditure and the need for vigorous
breathing (25). Perhaps the lowered body temperature
is, in part, a consequence of relative hypoxia. Some
plants, e.g., the Eastern skunk cabbage, and some
philodendra are able to maintain the temperature of
the spadix or inflorescence well above ambient temperature during flowering. This elevated temperature is
regulated to some degree and maintained by the appropriate alteration of the metabolic rate. The response
appears to be hormonally mediated (45, 57). However,
the sensory trigger for this thermal response awaits
full elucidation at the molecular level. Some of the key
elements of thermoregulation and fever are discussed
below.
HISTORICAL PERSPECTIVES
J Appl Physiol • VOL
COORDINATION OF THERMAL INPUTS
The hypothalamus plays a vital role in controlling
body temperature by coordinating thermal information
from all body areas and directing the efferent signals to
the appropriate heat production and heat conservation
systems in mammals. The evidence for this comes from
electrical stimulation and recordings (7, 33, 43) after
parts of the hypothalamus were thermally stimulated
and after hypothalamic lesioning (9, 31, 43). Hypothalamic disease has been found to be accompanied by
disordered temperature regulation (26). The neurons
in the anterior hypothalamus and the preoptic region
may respond to thermal stimulation directly or to thermal stimulation of other connecting neurons. Boulant
(10) proposed a hierarchy of neural structures controlling body temperature involving the brain stem and
spinal cord, with the preoptic area acting as the highest coordinating center.
Evidence about the neurotransmitter substances
used in hypothalamic and brain stem thermoregulatory synapses, particularly catecholamines and serotonin, was found in the 1960s (16, 24). Dopamine,
GABA, glutamate, and acetylcholine were also found
to be used as thermoregulatory neurotransmitters
(9). The search for these neurotransmitters was
spurred by Carlsson and colleague’s discovery of
norepinephrine in the hypothalamus by visualization with the formaldehyde condensation technique
(quoted in Ref. 15, p. 22) and by pharmacological
demonstration of high concentrations of catechol and
other amines in the hypothalamus (1, 73). Bligh (9)
proposed a neuronal model for sheep in which input
from warm receptors acting through serotoninergic
synapses evoke heat loss mechanisms and from cold
receptors acting through cholinergic synapses evoke
heat production and conservation. In this model are
cross-over neurons, possibly adrenergic, arranged so
that on warm stimulation the cold receptor pathway is inhibited and vice versa. This system may be
expanded to include synapses that use other neurotransmitters, with the transmitters varying according to the species. More recent evidence points to the
role of nitric oxide in both normal thermoregulation and fever. These roles are presented and discussed by Gerstberger (27). Nitric oxide appears to
be involved both in the central nervous system thermoregulatory regions and in the adjustment of peripheral vascular tone involved in temperature regulation. Cleavage of the heme molecule releases
carbon monoxide. There is evidence that within the
central nervous system carbon monoxide has a pyrogenic action (69). Although the prostaglandin E
pathway in the appropriate central nervous system
regions is central to the induction of fever, it is open
to speculation whether the nitric oxide and carbon
monoxide mechanisms provide an alternative fever
pathway. Such a suggestion is yet to be validated.
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receptors increase their discharge rate as the temperature falls (39). Both types of receptors show peaks of
activity with a fall in discharge frequency beyond the
peaks. The dynamic response of the warm receptors
involves a short-lived burst of firing when the temperature is abruptly raised, whereas that of the cold receptor involves a transient rapid fall in firing frequency. The transduction of the temperature stimulus
to neuron firing has been the subject of much study.
Which ion channels are involved is still debated. One
recent paper (51) provides evidence that a two-pore
domain mechanogated potassium channel called
TREK-1 may be one of the physiological temperature
receptors. The roles of membrane proteins and second
messenger substances in translating the opening of ion
channels into nerve impulses are still under intensive
investigation.
Downey et al. (22), using cooling cuffs around
arteries, found evidence for thermosensitivity in the
internal carotid artery of the rabbit. The use of direct
neuronal recordings has also provided evidence for
thermosensitive structures within the brain. Both
“cold” and “warm” thermosensitive neurons were
found in the hypothalamus, brain stem, and spinal
cord (33, 35, 58, 67). It is interesting that the range
of firing of cold receptors in the hypothalamus seems
to be wider in hibernating animals (75). Hori (38)
studied the transduction mechanisms of thermosensitive neurons in the preoptic area. He found that
warm-sensitive neurons developed a tetrodotoxinsensitive sodium current with a high Q10, whereas
cold-sensitive neurons experienced membrane depolarization due to reduction in potassium conductance. Boulant (11) studied the characteristics of
hypothalamic thermosensitive neurons and the action of such endogenous substances as pyrogens,
which reduce the activity of warm-sensitive neurons
and increase the activity of cold-sensitive neurons.
He also used a fluorescent dye (lucifer yellow) to
show that dendrites of warm-sensitive neurons are
arranged perpendicular to the third ventricle,
whereas the temperature-insensitive neurons lie
parallel to the third ventricle. This observation will
be very useful in developing models of hypothalamic
thermosensitivity. Boulant’s and other laboratories
have also used axonally transported markers; perhaps some of the mystery of the afferent and efferent
pathways used in thermoregulation will soon be unraveled. Burgoon and Boulant (13) investigated the
thermosensitive properties of some neurons in the
rat suprachiasmatic nucleus. Such neurons could be
important in providing clues to the mechanisms of
circadian clock synchronization. This interesting
physiological process requires further study as a
means to build bridges between observations at the
cellular level and the function of the whole animal.
Thermosensitive neurons may exist in other deep
body structures, and the weight given by the central
controlling mechanism(s) to inputs from all areas of
the body is still open to argument.
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There is evidence of the involvement of a histaminergic system involved in the brain stem subserving
mechanisms of hibernation (60).
THE “SET POINT”: ITS NATURE AND
EVOLUTIONARY SELECTION
Fig. 1. A schema for the controlling and controlled systems for the regulation of internal body temperature. ARAS,
ascending reticular activating system; Aud vis, audiovisual; CNS, central nervous system; T, temperature; hypo,
hypothalamus; ak, proportionality factor for nonevaporative heat transfer; am, proportionality factor for shivering;
EHL, evaporative heat loss; HP, heat production; HL, heat loss; K, coefficient for nonevaporative heat transfer; Tc,
core temperature; Top, operative temperature. [With permission from the Annual Review of Physiology, vol. 30,
copyright 1968 by Annual Reviews, www.AnnualReviews.org (Ref. 30).]
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The notion of a regulated body temperature was
clearly held by early researchers such as Currie (18),
Liebermeister (49), Ott (59), and Lefèvre (48). Simple
experiments in which human and animal subjects
were first immersed in cold or hot water until their
core temperatures changed and then put into a neutral thermal environment showed that the core temperature always returned to the initial level. The
idea that, during fever, vide infra, the body regulates
its temperature at a new high controlled level or “set
point” was also supported (15, 49). For humans, the
set point in health is ⬃37°C. The regulated level of
core temperature varies by ⬃1°C during the diurnal
daily temperature swing. The advantage to humans
of having a set point of ⬃37°C is unclear, especially
when considering the different “set” levels in other
mammals (range of 36–38°C), birds (38–43°C), marsupials (⬃35°C), and lizards during daylight hours
(⬃32–38°C) (15, 44). Simple organisms such as paramecium are capable of maintaining a “regulated”
temperature in a thermocline by selecting a thermal
environmental preferendum or possibly selecting a
region that avoids temperature extremes that would
be harmful (see above). The molecular “switch(s)” for
selection of thermal preferenda is still unclear. In a
recent study (14) of the nematode worm Caenorhabditis elegans, which has three pairs of neurons involved in temperature sensing, a gene (ceh-14) was
shown to confer thermosensory function. A groundbreaking model to explain the regulation of internal
body temperature was proposed (Fig. 1) by Hammel
(30), and he also used this model to develop a mechanism for a variable set point. Other engineering and
neuronal models of set-point mechanisms have also
been developed (see Chapters 11 and 12 in Ref. 9).
One of these suggests that the intersection of the
rising phases of the cold and warm receptors would
be at the set point. These models will probably continue to undergo modification as new facts are discovered. Core temperature set point follows a diurnal
cycle, changes during the menstrual cycle, and may
even be altered during exercise.
HISTORICAL PERSPECTIVES
SOME COORDINATED RESPONSES OF
MULTICELLULAR ORGANISMS TO THERMAL STIMULI
FEVER
An upward adjustment of the regulated temperature
is termed fever. Fever has important survival value
during infective disease. Studies of the genesis and
consequences of fever have made great strides over the
past half-century (see Refs. 8, 15, 20, 44, and 76). Fever
differs from an increase in core temperature, such as
that induced by hot baths or exercise in the heat. This
latter circumstance should be called “hyperthermia.”
The major breakthrough in our understanding of the
mechanism of fever came with the discovery by Beeson
(5) of “endogenous” pyrogen, which is released from
J Appl Physiol • VOL
white blood cells derived from sterile peritoneal exudates. This endogenous pyrogen was later found to be a
fairly low-molecular-weight (15–18 kDa) peptide. We
now recognize a family of cytokines; some of these,
such as interleukin-1␤ and tumor necrosis factor-␣, are
pyrogenic. Cytokines enable cells of the immune system to talk to each other. The release of pyrogenic
cytokines probably requires the action of the plasma
complement cascade (8). The locus of action was first
found to be in the vicinity of the anterior hypothalamus/preoptic region (15) and then more accurately
localized in the organum vasculosum laminae terminalis (OVLT) (see Ref. 70). The discovery of a role of
prostaglandin E as a final mediator of fever within the
hypothalamus added an important piece to the puzzle
of fever genesis (54). This notion was supported by the
fact that aspirin and other antipyretics block the synthesis of prostaglandin E2 (72). It is thought that either
the cytokines act within the OVLT to release prostaglandin E2, which then diffuses into the preoptic area,
or they activate neurons in the OVLT, which release
PGE2 in the preoptic area.
It has become apparent that fever is but one part of
a coordinated first-phase response to infection and that
the whole response includes mobilization of the immune system (20, 44). Kluger (44) showed that some
ectotherms and some mammals have a reduced survival rate if the animal’s core temperature is not allowed to rise. It may be that the benefits of fever to the
human are gained during the time between the onset of
infection and the patient seeking medical help. Nevertheless, the wisdom of early use of antipyretics in fever
is still debated.
A recent hypothesis was based on the absence of
fever in animals given intraperitoneal endotoxin after
subdiaphragmatic vagotomy. It was proposed that pyrogenic cytokines could act on vagal nerve endings in
the liver. A pathway through the brain stem to the
anterior hypothalamus/preoptic area then leads to the
release of PGE2 to cause fever (see Ref. 8). There is still
controversy over this proposition. Whether other peripheral neural inputs contribute to the initiation or
maintenance of fever has not yet been explored. Fever
caused by intravenous endotoxin in the human is often
accompanied by skin hyperalgesia and aching in muscles and joints. Whether these unpleasant symptoms
are caused by action of cytokines on peripheral nerve
endings or nerves or on the gating mechanisms in their
spinal or brain pathways remains virtually unknown
but worthy of study. The possible protective role of heat
shock proteins synthesized during fever is as yet little
understood. Brown (12) reported the synthesis of a
protein in the brain after induction of fever by bacterial
pyrogen that was similar to a heat shock protein.
Evidence for the release of arginine vasopressin into
the ventral septal brain area, where it acts as an
endogenous antipyretic, came from studies by Kasting
(42) after the discovery of the inability of newborn
lambs to respond to intravenous endotoxin with fever
(61). Other endogenous antipyretics include ␣-melano-
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An important response to changes in the environmental and body temperatures is the heat loss or
conservation behavior (65). Moving to warmer or cooler
places, donning or removing clothing, and adopting
heat-exchange-altering postures are examples of behavioral thermoregulation. Physiological responses
also occur (15, 36). These include alteration of the
distribution of blood flow between the core and the skin
so that surface heat loss is increased or reduced, the
initiation of additional heat production by shivering,
and the activation of nonshivering thermogenesis and
the reduction of heat production during heat exposure.
Physiological and behavioral responses to hypothalamic cooling were found to occur simultaneously in
female rats (see p. 158–163 in Ref. 65). During long
periods of cold exposure, some changes in basal metabolism are principally under the control of the thyroid
hormones. Nonshivering thermogenesis occurs particularly in specialized fat depots known as brown adipose tissue (BAT). These fat pads are found in the
newborn of several species and in adults of some animals. They are mainly located between the scapulae
and around the kidneys. These fat cells are smaller
than white fat cells, they contain high concentrations
of mitochondria, and have a dense sympathetic innervation. They have been studied since the 1960s (37,
68); however, Dawkins and Hull (19) reported that
Konrad von Gesner described brown fat in 1551. Recently, a group of proteins, the uncoupling proteins
(UCPs), has been identified. One of these, the brownfat-specific UCP-1, has been shown to be paramount in
mounting adaptive nonshivering thermogenesis in the
cold in mice (29). There may also be nonshivering heat
production in muscle or other tissues. Generation of
heat in BAT is of great importance to hibernating
animals as they rewarm. The ability of hibernators to
drop their core temperatures and be in a state of torpor
for long periods in winter and then to rewarm mainly
by using BAT is a unique adaptation. Hibernation
mechanisms have been discussed by Lyman (50). The
environmental and/or internal triggers for entering
and rousing from hibernation are not well understood,
and the gene switches for turning the BAT activation
on and off require much more study.
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cyte stimulating hormone (␣-MSH) (acting in the lateral septum) and corticosteroids (see Ref. 15).
HYPERTHERMIA
QUO VADIS?
Attempting to predict the future of any scientific
field is always dangerous. However, several lines of
investigation would appear useful. Use of modern imaging techniques can show brain areas that become
active during thermoregulatory responses or fever and
antipyresis. After the localization of such regions by
imaging, neurophysiological methods can be applied to
determine connectivity. The use of axonally transported markers such as microbeads, immunochemical
markers, and virus particles, which cross synapses,
will add to the studies of the circuitry. The gene
switches in the appropriate neuron pools and connecting neurons can then be related to thermoregulatory
function. In addition, use of these materials could lead
to identification of the range of ion channels in these
neurons. Ion channels in peripheral thermoreceptors
could then be revealed, as well as intracellular messenger systems that result from the ion fluxes. The use
of knock-out animals is already extensive and should
help unravel thermal mechanisms, such as the role of
cyclooxgenase-2 in fever (8) at the cellular level. However, it should be noted that, in multifactorial control
mechanisms, failure to prevent a function by one gene
knockout may only mean that subsidiary mechanisms
take over. Recent research has shown some gender
differences in thermoregulatory responses and fever.
More studies of these differences could lead to interesting knowledge of the actions of reproductive hormones in thermoregulatory circuits. Studies of the
mechanisms of hibernation at the cellular and gene
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Hyperthermia can occur naturally or it may be artificially induced, for example, as an adjunct to cancer
therapy. Naturally, it may occur during exercise in the
heat, particularly if sweating is inhibited. This can
occur if fluid intake or salt intake is restricted (46) or if
minute amounts of bacterial pyrogen are present in the
circulation (2).
Thermotolerance (heat resistance) can be related to
the gene activation of proteins termed heat shock proteins. These proteins have been widely studied by molecular biologists (66). An original observation was the
finding of stress-related genes activated on the Drosophila melanogaster salivary gland chromosome when
the fly was given a heat shock (64). The gene switches
for the synthesis of heat shock proteins and other
stress proteins have yet to be fully elucidated; this
discovery will add important information regarding
the mechanisms of thermotolerance and fever. Raising
oral or rectal temperatures in humans to 38.2–38.6°C
in a hot tub for as little as 15 min triggered heat shock
protein 72 gene expression (53). The possible therapeutic gains from this means of generating the protein
requires further study.
level could produce important knowledge about thermoregulatory control in both hibernators and nonhibernators. Perhaps other combinations of neurotransmitters will be found in thermoregulatory circuits, and
discovery of these could lead to development of new
drugs to manage thermoregulatory disorders. The combined role of fever and the immune system stimulation
needs much further investigation. Finally, nature presents lesions that, when studied, could lead to identification of new knowledge about basic functions. Close
collaboration with clinical colleagues will be of value.
The past 50 or so years have brought enormous increases in our knowledge of thermoregulatory function
and disorder, and truly the future of thermoregulatory
research looks very exciting as researchers integrate
the molecular aspects with the function of the whole
organism.
HISTORICAL PERSPECTIVES
J Appl Physiol • VOL
46. Kohgali M. Heat stroke: an overview, with particular reference
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