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Department of Physiology and Biophysics, University of Tennessee at Memphis, Memphis, Tennessee 38163; and Thermoregulation Laboratory, Legacy Research, Legacy Portland Hospitals, Portland, Oregon 97227
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Romanovsky, Andrej A., and Clark M. Blatteis. Heat
stroke: opioid-mediated mechanisms. J. Appl.
Physiol. 81(6): 2565-2570, 1996.
In our previous
study in guinea pigs, intensive and prolonged intraperitoneal heating
(IPH) caused heat stroke characterized by high mortality and
accompanied by two paradoxical phenomena: ear skin vasoconstriction at
a high body temperature (Tb)
(hyperthermia-induced vasoconstriction) and a post-IPH
Tb fall at an ambient temperature (Ta) below thermoneutrality
(hyperthermia-induced hypothermia). In this study, we tested the
hypothesis that the mechanisms of the two phenomena involve endogenous
opioid agonists. Experiments were conducted in 24 unanesthetized,
lightly restrained guinea pigs, each chronically implanted with an
intraperitoneal thermode and intrahypothalamic thermocouple. The
thermoregulatory effects of a wide-spectrum opioid-receptor antagonist,
naltrexone (NTX; 50 or 0 µmol/kg sc), were studied in IPH-induced
heat stroke and under normal conditions. IPH was accomplished by
perfusing (50 ml/min; 80 min) water (45°C) through the thermode.
Ta was maintained at ~24°C.
Skin vasodilation occurred at the onset of IPH but later changed to
vasoconstriction despite high Tb
and continuing IPH. IPH-induced hyperthermia (1.8 ± 0.1°C) was followed by a post-IPH Tb fall (
5.1 ± 0.7°C; calculated for the survivors only). The 48-h mortality rate
was 50%. NTX prevented the hyperthermia-induced vasoconstriction and
attenuated the hyperthermia-induced hypothermia (1.8 ± 0.4°C). None of the NTX-treated animals died. The effects of NTX on
Tb regulation under normal
conditions were minor. These results indicate that the phenomena of
both hyperthermia-induced vasoconstriction and hyperthermia-induced
hypothermia are opioid dependent. The latter is speculated to reflect
opioid-mediated inhibition of metabolism; the former is thought to
result from opioid-induced hemodynamic alterations. Because both
phenomena did not occur in the NTX-treated survivors, the skin
vasoconstriction at high Tb and
the posthyperthermia Tb fall may
be viewed as markers of the severity of heat stroke. It is suggested
that opioid antagonists may have therapeutic potential in heat-induced
disorders.
hyperthermia; hypothermia; poikilothermia; vasoconstriction; vasodilation
INTRODUCTION IN OUR PREVIOUS STUDY in guinea pigs (25), intensive
and prolonged intraperitoneal heating (IPH) caused a pathological
sequela characterized by high mortality (heat stroke). This IPH-induced heat disorder was accompanied by two paradoxical
thermoregulatory phenomena. First, although ear skin vasodilation
readily occurred at the onset of the IPH-induced hyperthermia, it later
changed to vasoconstriction, despite the continuing IPH and high body temperature (Tb); we termed this
phenomenon "hyperthermia-induced vasoconstriction." Secondly,
when IPH was stopped, the initial hyperthermia was followed by not just
a return of Tb to its pre-IPH level but by its fall to below this level; we termed this phenomenon "hyperthermia-induced hypothermia."
The aim of the present study was to test the hypothesis that the
mechanisms underlying the two heat stroke-associated paradoxical thermoregulatory phenomena involve endogenous opioid agonists. Opioids
possess a variety of thermoregulatory actions (1, 27), participate in
fever genesis (6, 27), and are implicated in the mechanisms of heat
adaptation (13, 29). They have also been proposed to play a role in the
pathogenesis of shock (see Ref. 12 for review). Thus naltrexone (NTX),
a wide-spectrum opioid-receptor antagonist with a strong
anti-µ-receptor activity, and naloxone, its
N-allyl congener with a shorter
duration of action, have each been demonstrated to lessen the severity
of shock of various etiologies, including endotoxin shock (9) and heat
stroke (21). A four-fold increase in the plasma level of
To address our aim, we applied IPH to unanesthetized guinea pigs and
studied the effect of NTX on the IPH-induced pathological sequela.
METHODS
-endorphin/-lipotropin (the most abundant endogenous µ-receptor opioid agonist) has been recorded in patients with heat stroke (4).
T, intraperitoneal thermode
output-input temperature gradient;
Ta, ambient temperature; Th, hypothalamic temperature; and
Tsk, ear skin temperature. Open arrows, water flow direction; solid arrows, signal transduction.
Experimental protocols. The study was designed to evaluate the effect of NTX on thermoregulatory symptoms of IPH-induced heat stroke. For this, NTX-HCl (Research Biochemicals International, Natick, MA) was injected (0 or 50 µmol/kg sc) in pyrogen-free saline (PFS; 1 ml/kg) immediately before the beginning of IPH. To differentiate the effect observed in heat stroke with the drug's action in normothermia, two other groups of animals were injected with the same doses of NTX (0 or 50 µmol/kg), but no IPH was performed. The 50-µmol/kg dose of NTX was chosen as the dose minimally affecting thermoregulation of guinea pigs under the normal conditions (causing ~ 0.5°C drop in Tb) in a pilot study. In all the experiments, hypothalamic (Th), ear skin (Tsk), and ambient (Ta) temperatures were monitored from 1 h before until at least 9 h after the NTX administration. All three temperatures were used to assess changes in the thermoregulatory vasomotor tone (see Data processing and analysis below). Th was also used as an index of Tb and, for this purpose, was preferred over traditional indexes (such as rectal, colonic, and esophageal temperatures) to insure the minimal possible "contamination" of the measured temperature by the procedure of IPH per se. All thermocouples were scanned once a minute, and the data were displayed both graphically and digitally and stored on a disk. Ta was maintained at ~24°C. Animals were observed for 48 h after the experiment. Model of heat stroke. Heat stroke was induced by IPH. The advantage of this method (as compared with the commonly used exposure to a high Ta) is a better standardization of the heat load; this advantage can be developed even further if the technique of feed-forward control (described for the case of intraperitoneal cooling; see Ref. 24) is used. IPH was performed by perfusing water at an inflow temperature (Tin) of 45°C through the thermode; the perfusion rate was 50 ml/min, and the perfusion duration was 80 min. Tin was checked every 1 min and, if necessary, adjusted. The difference between the outflow temperature and Tin was also recorded every 1 min (to verify the efficiency of IPH). The total heat load delivered over the entire 80-min period was ~5 kJ. The maximal temperature to which the internal organs of the animal were actually exposed during IPH was determined in a separate experiment on an anesthetized guinea pig implanted with an intraperitoneal thermode (2 wk before the experiment) and an intraperitoneal thermocouple (inserted immediately before the experiment and attached to the wall of the isolating "bursa" formed by the greater omentum). The abdominal temperature was 2.5-2.8°C lower than Tin at the beginning of IPH and 1.2-1.5°C lower than Tin at the end of the procedure. The actual temperature to which the internal organs were exposed never exceeded 43.9°C. This is comparable with the solution temperature of 45°C recommended for intraperitoneal dialysis in hypothermic infants (10). Data processing and analysis. To assess the changes in the peripheral vasomotor tone, the heat loss index (HLI) was calculated according to the formula
|
(1) |
Th
and HLI, respectively) over time and comparing the integrals between
the groups with the help of the unpaired Student's
t-test. The mortality data were
evaluated by using Fisher's exact test.
RESULTS
The initial thermal state of the guinea pigs was characterized by normothermia (the mean initial Th for all experiments was 38.3 ± 0.2°C) and moderate skin vasoconstriction (the mean HLI value was 0.49 ± 0.02).
Intensive and prolonged IPH caused heat stroke with a 50% mortality
rate (3 of 6 animals died). The thermoregulatory responses to IPH are
shown in Fig. 2 (data from a single
experiment in a survivor) and Fig. 3
(averaged data from all of the experiments of the series). These
responses to IPH included both the hyperthermia-induced hypothermia and
hyperthermia-induced vasoconstriction phenomena. IPH-induced
hyperthermia (maximal Th of 1.8 ± 0.1°C at 48 ± 7 min after the beginning of IPH) was later
followed by a post-IPH Th fall
(Th of 5.1 ± 0.7°C at 302 ± 20 min; calculated for the survivors only). In
the survivors, the hypothermia lasted for at least 15 h (the longest
recording period) but probably not much longer than this (the duration
can be approximated from Fig. 2). Skin vasodilation (maximal HLI of
0.95 ± 0.01) occurred at the onset of IPH (6 ± 1 min) but later
changed to vasoconstriction (HLI dropped to 0.44 ± 0.04 at 36 ± 4 min), despite continuing IPH. An important characteristic of the
latter phenomenon was its independence of
Th: the whole transition from
maximal vasodilation to constriction took place at the same
Th (~40.0°C; Fig.
4).
Th, changes in
hypothalamic temperature; HLI, heat loss index; n = no. of
animals. Three of 6 animals in control group (IPH + NTX, 0 µmol/kg
sc) died after time-marker (
); all 5 guinea pigs in the
experimental group [IPH + NTX (50 µmol/kg sc)] survived
for at least 48 h after IPH.
At the dose used, NTX did not affect the development of the IPH-induced
hyperthermia but attenuated and shortened the post-IPH hypothermia (the
maximal drop of Th was only 1.8 ± 0.4°C, occurring at 199 ± 2 min; the hypothermia lasted
for ~10 h) and completely prevented the
hyperthermia-induced vasoconstriction (Figs. 2 and 3). Comparison
between the integrals of Th
over the time period 102-120 min after the injection showed that
the effect of NTX on the hyperthermia-induced hypothermia appeared to
be statistically significant (P < 0.03). To evaluate the effect of NTX on the hyperthermia-induced vasoconstriction, HLI was integrated over the time period 0-102 min after the injection, and the integrals were compared between the
two groups; this effect also appeared to be significant
(P < 0.02). Not only did
the transition from vasodilation to constriction occur much later in
the NTX-treated animals (Figs. 2 and 3), but the
Th dependence, which is normally
characteristic of the skin vasomotor tone, also was restored (Fig. 4).
Another important result of this study was that all five animals
treated with NTX survived the IPH for the entire observation period (48 h). Although the difference in the mortality between the NTX-treated
and nontreated groups did not reach statistical significance, the
obtained value of P (< 0.18) could
be regarded as suggestive. The experiments with IPH were then
terminated for humane reasons.
Despite the high magnitude of the thermoregulatory effects of NTX in
the IPH-treated animals, the drug's effect on
Tb regulation under normal
conditions was minor (Fig. 5). Indeed, in
the animals that were not subjected to IPH, NTX caused only a slight
decrease of Th (0.5 ± 0.1°C at 40 ± 4 min postinjection), and no change in HLI
occurred at the Ta used
(24°C).
Th and HLI of guinea pigs
injected subcutaneously with NTX at doses indicated.
DISCUSSION
)-stereoisomer of naloxone (binds to opioid
receptors) but not by the (+)-isomer (does not bind to opioid
receptors) (9). Our conclusion about the involvement of opioids in the
mechanisms of the hyperthermia-induced vasoconstriction is in general
agreement with the literature. Thus, endogenous opioid peptides are
released into the blood in response to various stressors, including
heat; exogenous opioid agonists, even in small doses, induce
hypotension; and opioid antagonists block hemodynamic alterations in
various models of shock (see Ref. 12 for review). Yet the intimate
mechanisms of the effect of opioid antagonists on the
hyperthermia-induced vasoconstriction, the specific role of endogenous
opioids in this phenomenon, and pharmacological characterization of the
opioid receptors involved remain to be elucidated.
Hyperthermia-induced hypothermia.
Confirming our previous results (25), the cessation of IPH did not
result in just a return of Th to
its pre-IPH level but rather was followed by the development of
hypothermia. This phenomenon, termed hyperthermia-induced hypothermia,
has been demonstrated in various experimental models and in different
animal species. Thus not only IPH in guinea pigs (25) but also whole
body heat exposure in guinea pigs (2), rats (19), mice (33, 34), and
cats (2), as well as IPH in rats (28), all result in a
Tb fall occurring after the
heating is stopped.
A priori, the thermoregulatory mechanisms of the hyperthermia-induced
hypothermia could involve: 1)
inhibition of metabolism; 2)
excessive heat loss (e.g., generalized peripheral vasodilation) that
cannot be compensated for by an increase in heat production; 3) regulation of
Tb at a new, decreased level
(parallel shifts of thermoeffector thresholds to a lower
Tb);
4) a substantially decreased
precision of Tb regulation
(development of the wide dead-band, poikilothermic type of control)
when Ta is below thermoneutrality; or 5) partial contributions of
several of the mechanisms listed above. It has been demonstrated that
hyperthermia-induced hypothermia occurs at low but not high
Ta (33). It has also been shown
that this phenomenon is associated with the widening of the
interthreshold zone (poikilothermia), probably as a result of a
decrease of the threshold Tb for
cold thermogenesis (unpublished observations; see also Ref. 25). We
speculate, therefore, that this metabolic inhibition and the consequent
widening of the interthreshold zone constitute the major autonomic
mechanisms of hyperthermia-induced hypothermia. It is worth noting that
these are exactly the same mechanisms that have been recently found to
underlie the hypothermia of endotoxin shock (26).
The present results further demonstrate that hyperthermia-induced
hypothermia is opioid dependent because NTX significantly attenuates
this phenomenon. If our concept of the thermoregulatory mechanism of
post-IPH hypothermia were correct, this would imply that endogenous
opioids are involved in the proposed metabolic inhibition. This
corollary is in agreement with the existing literature. Indeed, opioids
are known to inhibit metabolism and cause hypothermia at
Ta below thermoneutral (8, 18).
The opioid receptor subtype mediating the metabolic inhibition remains
to be determined.
Potential clinical significance.
Despite continuing economic development, technical progress, and
medical advances, heat stroke remains an important clinical issue. It
is pertinent not only to the Makkah Hajj, a famous pilgrimage to Mecca
resulting in hundreds of deaths due to heat stroke each year (7, 15),
but to our everyday life as well. In the United States, during hot
summers, an average of 820 deaths are caused annually by
heat injury, with at least 10 times more due to cardiovascular problems
exacerbated by heat stress (3). Our present results may have potential
clinical applications.
Among the symptoms that have traditionally been used to define heat
stroke is high Tb
(>40.6°C). This criterion should not, however, be
considered obligatory because many patients with severe exertional heat
stroke have lower Tb, presumably
due to the progression of time from the actual heat overload (7). Our
present data and several other experimental observations (2, 19, 25, 28, 33, 34) suggest that if the heat exposure is followed by the return
of the animal to a near-thermoneutral environment, hypothermia rather
than hyperthermia is likely to be recorded. Moreover, the longer and
more intensive the initial heat exposure is, the deeper and longer is
the consequent hypothermia (25, 33). It is noteworthy that all of the
NTX-treated animals in the present study developed only a very mild
post-IPH hypothermia and survived heat stroke, whereas deep hypothermia
and 50% lethality were observed among the nontreated controls. We
propose that when a patient with heat stroke is exposed to an
Ta below thermoneutrality, a
Tb fall may occur; this fall
(hyperthermia-induced hypothermia) can be taken as a marker of the
severity of heat stroke.
Another common symptom of heat stroke, a hot and dry skin, indicates
the absence of sweating. Although there are several opinions about the
mechanisms and significance of the cessation of sweating in heat stroke
(see Ref. 7), the consensus is that the disappearance of this heat-loss
response worsens the patient's prognosis. Similarly to the cessation
of sweating, the reversal of skin vasodilation to vasoconstriction
occurring at a high Tb
(hyperthermia-induced vasoconstriction) may be taken as an index of the
severity of heat stroke. In the present study, survival from heat
stroke by NTX-treated animals was accompanied by the blockade of the
hyperthermia-induced vasoconstriction.
An important result of this study is that all the guinea pigs treated
with NTX survived IPH-induced heat stroke for the whole period of
observation (48 h). This agrees with earlier reports that naloxone, an
opioid-receptor antagonist with pharmacological properties similar to
NTX, substantially increased the survival time in rats exposed to heat
(21) and prevented hyperthermia-induced convulsions in rat pups (23).
In consideration of the high levels of plasma -endorphin in Mecca
pilgrims with heat stroke (4), the antipyretic properties of naloxone
(6, 27), and the beneficial effects of opioid antagonists in shock of
various etiologies (12), it may be inferred that the blockade of
endogenous opioids in heat stroke has a therapeutic potential.
The majority of studies on the role of the opioid system in the
thermoregulatory response to heat, including the present work, were
performed with the use of nonselective opioid antagonists such as
naloxone and NTX. This design increases the probability of discovering
a new effect because of the multiple actions (both direct and indirect)
of opioids on autonomic and behavioral thermoregulation. One of the
priorities for future investigations, however, should be the
determination of the receptor type(s) mediating beneficial effects of
opioids in heat stroke.
ACKNOWLEDGEMENTS
We thank Drs. W. S. Hunter and L. D. Partridge for methodological suggestions, L. D. Homer for the statistical analyses, and V. A. Kulchitsky for his comments on the manuscript. Graphic assistance by L. A. Malinic and editorial assistance by R. S. Hunter are appreciated. Special thanks to C. T. Simons for his help with several aspects of this work.
FOOTNOTES
Address for reprint requests: C. M. Blatteis, Dept. of Physiology and Biophysics, Univ. of Tennessee at Memphis, Memphis, TN 38163.
Received 26 February 1996; accepted in final form 19 August 1996.
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