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-induced fever in young and old Long-Evans
rats
1 Department of Biological Sciences, 3 Department of Psychology, and 2 Program in Neuroscience, University of Delaware, Newark, Delaware 19716-2590
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Aging is
associated with a blunted or absent fever response to naturally
occurring infections or to the peripheral administration of bacterial
products and proinflammatory cytokines, including interleukin-1
(IL-1). Whether old rats also exhibit an attenuated fever response
when challenged with direct brain administration of IL-1 is unknown.
Here we investigated the fever response of young (3-5 mo) and old
(24-26 mo) Long-Evans rats to the intracerebroventricular microinfusion of IL-1. Core body temperature was monitored by telemetry in freely moving rats. Intracerebroventricularly administered IL-1 induced comparable increases in body temperature in young and
old Long-Evans rats. In the two groups, IL-1-induced fever was
similar both in latency to peak fever and maximal fever response, whether the cytokine was administered 2 h after lights on or just before lights off. These data show that old Long-Evans rats are not
defective in their capacity to develop a fever in response to brain
administration of IL-1.
cytokine; intracerebroventricular; aging; core temperature; nervous system; immune system
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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INTERLEUKIN (IL)-1 is a proinflammatory cytokine
that induces fever (2, 11, 14). In rodents, when IL-1 is
administered intracerebroventricularly, low-nanogram doses are
sufficient to induce fever. When IL-1 is administered peripherally,
microgram doses are required to induce equivalent fevers. This suggests that the pyrogenic effects induced by low doses of centrally
administered IL-1 are due to its direct action in the central
nervous system (CNS).
Aging is associated with alterations in the host physiological
responses to inflammatory and infectious stimuli (4). Often, elderly
patients show a blunted fever or no fever at all in response to
infection (18). The same is true in old rodents: peripheral (intraperitoneal, intravenous) administration of bacterial products or
proinflammatory cytokines (1, 8, 16, 17, 28), including IL-1 (19,
27), is associated with a blunted fever response. Delayed febrile
responses to peripheral immunological challenges have also been shown
in old rats (8, 22).
Young rats centrally injected with IL-1 respond with fever (25, 29).
However, whether old rats respond with fever after such a procedure is
unknown [studies in aged rabbits reported that central injection
of a crude supernatant containing IL-1 and other
lipopolysaccharide-induced cytokines produced a blunted fever response
(6, 15); however, use of a crude preparation containing multiple
cytokines precludes any conclusion on the role of IL-1]. If
old rats did not become febrile, it would suggest that they do not have
the physiological ability to make fever responses. If they did become
febrile, it would imply that they have the capacity to develop a fever,
but peripheral administration of bacterial products or proinflammatory
cytokines including IL-1 does not activate the required sequence to
initiate the fever response. Here we report that after
central administration of IL-1, old Long-Evans rats develop fevers
just as well as do young rats, although they do not maintain the
elevated body temperature for as long.
Body temperature in rats is a diurnal rhythm, lower in the morning than
in the evening. In earlier work in young rats, we demonstrated that
after central injections of prostaglandin
E2, peak body temperatures
attained were similar even when the injections were made 12 h apart
(7). Those results showed that central injections of prostaglandin
E2 raise body temperature to a
particular level, independent of either the body temperature at the
time of the injection or the phase of the light-dark cycle (7). To
determine the generalizability of these results, we administered the
IL-1 at two different times, just before lights off and 2-2.5 h
after lights on. We report here that peak body temperatures attained
were similar at the two different infusion times.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Subjects and maintenance. Male young (3-5 mo) and old (24-26 mo) Long-Evans rats were used. They were housed individually and maintained on ad libitum powdered rat food (Labdiet, PMI Feeds, St. Louis, MO) and tap water (26). Lights were on from 0700 to 1900, and room temperature was kept at 23 ± 1°C. All rats were handled daily.
Implantation of brain cannulas.
Rats were anesthetized with intraperitoneal injections of ketamine (100 mg/kg) and xylazine (5 mg/kg). A 23-gauge guide cannula was implanted
into the third cerebral ventricle at the following stereotaxic
coordinates: 
2.1 mm anteroposterior and 0.0 mm lateral with
respect to the bregma and 7.5-8.0 mm dorsoventral from the brain
surface, as in previous studies (20). An incision was made through the
dura mater with a dural hook. The superior sagittal sinus was carefully
pulled to one side, and the 23-gauge guide cannula was gently lowered.
Once the cannula was in position, the retraction of the sinus was
released and the cannula was anchored with dental acrylic. The location
of the cannula tip in the third ventricle was verified by the free
outflow of cerebrospinal fluid (CSF) through the guide cannula. A
sterile 29-gauge stainless steel obturator was used to ensure
that the cannula remained patent.
Intracerebroventricular microinfusion.
At least 14 days postoperatively, the first microinfusions were made
into the third ventricle. The third ventricle was chosen because of its
proximity to the hypothalamus and the importance of hypothalamic brain
regions in thermoregulation. Intracerebroventricular microinfusions (10 µl/rat) were at the rate of 1 µl/60 s using a Harvard infusion pump
(Harvard Apparatus, South Natick, MA). The intracerebroventricular
microinfusions were done between 0900 and 0930 (i.e., 2-2.5 h
after lights on) and between 1830 and 1900 (i.e., 0.5 h to just before
lights out). All rats received a control infusion of heat-treated
IL-1, followed 3 or more days later by infusion of intact IL-1.
These two infusions were repeated at least 2 wk later at the other time
of day. The first active IL-1 infusion was in the early evening.
(4.0 ng/rat; R and D Systems, Minneapolis,
MN)1
was used for all studies. This dose was selected based on our previous
studies showing that it induces significant anorexia in rats (21, 26).
The same IL-1 lot and stock solutions were used for all experiments.
IL-1 was dissolved in sterile physiological saline (0.15 M NaCl)
containing 2.0 µg/10 µl BSA (J. R. H. Biosciences, Lenexa, KS)
[2.0 µg/10 µl is equivalent to the concentration of albumin
normally present in the CSF (3)]. BSA was added because of its
properties as a stabilizing agent and carrier protein for cytokines
(21). Heat treatment and verification of IL-1 inactivity were done
as in previous studies (26). Each test solution was administered in a
10-µl volume and had a pH of ~7. To avoid nonspecific adsorption of
IL-1 on the experimental tools, we siliconized all such materials.
After an experiment was completed, rats were anesthetized with
CO2 and decapitated and the
position of the cannula tip in the third ventricle was verified.
Measurement of body temperature. Body temperature was measured by a biotelemetry system (Mini-Mitter, Sunriver, OR) using precalibrated transmitters implanted intra-abdominally at the time of the intracerebroventricular cannulation. The transmitter output (accuracy of ±0.1°C, frequency in Hz) was monitored by an antenna in the receiver board placed under each rat's cage. The output signals were fed into a consolidation matrix processor connected to a PC-based analog-to-digital conversion system (DataCol version 3 data acquisition system) and were converted into degrees Celsius as in our previous studies (28). The body temperature of each undisturbed rat was monitored continuously at 5-min intervals. After the rats were killed, the transmitters were recalibrated to verify calibration temperatures.
Data analyses.
Results are expressed as means ± SE. Experiments showed that the
intracerebroventricular infusion of heat-treated IL-1 increased body
temperature (Fig. 1, A and
B). Therefore, to obtain the net effect of IL-1, we subtracted the body temperature changes induced by the heat-treated (inactive) IL-1 from those induced by the active
IL-1. This subtraction was done on an individual basis, that is,
within a rat, for all time points before generation of the data in Fig.
2, A and
B.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In the morning, the mean body temperatures of both groups of rats for
the 2-h preinfusion period were similar (Fig.
1A):
37.46 ± 0.19°C for young rats and 37.45 ± 0.21°C for
old rats receiving active IL-1. In the evening, body temperatures
were slightly higher than in the morning, but there was no difference
between the two groups (Fig. 1B):
37.67 ± 0.16°C for young rats and 37.65 ± 0.10°C for
old rats receiving IL-1.
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In the morning, body temperatures began to rise ~30 min preinfusion,
which is when the door to the animal room was opened and preparations
for the infusions were begun. For the first 2 h postinfusion, at both
times of day, the body temperature responses to IL-1 of the old rats
were indistinguishable from those of the young rats in both latency to
peak fever and initial fever height (Fig. 1,
A and
B). After approximately the first
2 h, the body temperature of the young rats declined, whereas
the body temperature of the old rats remained high for an additional 2 h. The old rats were also more responsive to the heat-inactivated IL-1 injections, from 120 min postinfusion at both times of day.
The way the data are presented in Fig. 1,
A and
B, suggests that the old rats were
more responsive to the IL-1 infusion, because their body temperature
remained significantly higher than that of the young rats from 120 to
240 min postinfusion. However, this is misleading, because old rats
were also more responsive to the heat-inactivated IL-1 preparation.
Therefore, the proper comparison may be that shown in Fig.
2, A and
B. This figure shows the net changes
in body temperature before and after infusions of active and inactive
IL-1 in old and young rats in the morning and evening for 12 h
postinfusion. Figure 2 makes it clear that there are no differences
between young and old responses for the first 240 min.
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In the morning, IL-1 increased body temperature above baseline in
both young [H (with
1 degree of freedom) = 8.22, P = 0.004] and old [F(1,12) = 25.6, P = 0.0003, power of performed
test (ppt) = 1.0] rats from 80 to 240 min (Fig.
2A). The body temperature response
was similar in latency to peak fever and maximal effect observed
[F(1,16) = 0.0, P = 0.89]. After that, the body
temperature of the young rats remained significantly above baseline for
540 min [H (with 1 degree of
freedom) = 11.2, P = 0.0008]
(Fig. 2A). The old rats exhibited a
different profile: after the initial fever response, which lasted up to
240 min, their body temperature decreased below baseline from 260 to
600 min. This differential profile between old and young rats from 260 to 540 min was significant (P < 0.001).
For the evening infusions, the curves are very similar (Fig.
2B). From baseline, IL-1 induced
a significant increase in body temperature during the 80- to 240-min
period in both young [F(1,12) = 13.9, P < 0.003, ppt = 0.93]
and old [F(1,12) = 45.8, P < 0.0001, ppt = 1.0] rats.
The fever profile (including latency to peak fever) was similar in both
groups [F(1,16) = 1.58, P = 0.23]. From 360 to 560 min
after IL-1 administration, both young and old rats exhibited a
similar tendency to a lower body temperature. However, this was
significant only in the old rats (P < 0.03 from 420 to 540 min relative to baseline).
Figure 3,
A and
B, illustrates that there is no
difference between the fever time course profiles after morning or
evening infusions for both young and old rats. Preinfusion body
temperature is higher in the evening in both groups. Nevertheless,
postinfusion body temperatures in response to IL-1 were equivalent
whether IL-1 was administered during the morning or just before
nighttime.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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These data demonstrate that old Long-Evans rats are not defective in
their capacity to develop a fever in response to the intracerebroventricular administration of IL-1. The IL-1-induced fever profile was similar in latency to peak fever and maximal fever
height in both old and young rats during the first 4 h postinfusion.
The differences between the two groups started at ~260 min
postinfusion after the morning IL-1 administration. The young rats
maintained the increase in body temperature for 540 min after IL-1
administration, whereas the old rats exhibited a decrease relative to
baseline from 260 min. This suggests that although young and old rats
have similar responsiveness to brain IL-1-induced pyrogenesis, their
thermoregulatory modulation is not the same.
The mechanisms for the dissimilar time course profile shown in Fig. 2,
A and
B, are unknown. Young and old rats may
have distinct clearance and/or uptake mechanisms for IL-1 or
different levels of cytokine antagonists and endogenous antipyretic
peptides. Indeed, in humans, concentrations of IL-1 receptor
antagonist (an endogenous competitive inhibitor of IL-1 action) are
elevated in healthy aged subjects relative to young ones (4, 23). Both
old humans and old rodents exhibit higher activity of CNS antipyretic
pathways (e.g., vasopressin). For instance, hypothalamic vasopressin
mRNA and vasopressin production increase with age (5, 10) and IL-1
stimulates vasopressin release (12, 29, 30). Moreover, there are
changes in the hypothalamic-pituitary-adrenal axis that may also
contribute to differences between young and old rats. For example, in
old rats, once a stress response is elicited, it takes longer to return
to baseline (24), and data also suggest that there is a profound
dysregulation of the hypothalamic-pituitary-adrenal axis in aging (9).
For both young and old rats, the absolute body temperatures reached were the same in the morning and in the evening, although the baseline body temperatures were lower in the morning. These data agree with earlier work showing similar responses to the central injection of prostaglandin E2 (7). Thus, after central injections of two pyrogenic compounds, the change in body temperature is controlled to achieve the same regulated fever height.
Perspectives
The present studies show that after central administration of IL-1,
old rats develop an immediate fever response that is very similar to
that of young rats. Therefore, the lack of fever or delayed onset of
fever reported previously after peripheral administration of bacterial
products or proinflammatory cytokines, including IL-1, in old rats
is due to an inability of immunological challenges to activate the
required sequence of events from the periphery rather than to an
unresponsiveness of brain systems to stimulate the appropriate
physiological heat-producing and heat-conserving mechanisms.
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ACKNOWLEDGEMENTS |
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Research was supported by funds from the University of Delaware and by National Institute of Mental Health Grants RO1-MH56082 to C. R. Plata-Salamán and RO1-MH41138 to E. Satinoff.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
1
We estimated that a dose of 4.0 ng IL-1/rat
administered intracerebroventricularly will be at the interface between
the pathophysiological and suprapathophysiological range. The rat's
normal CSF volume is ~300-400 µl. We estimate that the
concentration of IL-1 in the CSF, if not metabolized, will be
100-133.3 pg/10 µl after a dose of 4.0 ng IL-1. Furthermore,
considering the rat's normal rate of CSF turnover and secretion to be
~0.7% of the total volume/min [based on a CSF production rate
of 1.99 ± 0.16 µl/min (mean ± SD from 3 studies; see Ref.
26)], the concentration of IL-1 120 and 240 min after 4.0 ng
IL-1 administration would be ~43 and 18.5%, respectively, of the
initial amount; that is, 43.2 and 18.8 pg/10 µl for a volume of 400 µl and 57.6 and 24.8 pg/10 µl for a volume of 300 µl at 120 and
240 min, respectively. In these calculations,
CT = 10[S(1 K)T]/V, where
CT is the concentration after
time T (min), 10 is 10 µl, S is the
amount of test substance administered (here 4.0 ng IL-1), K is the
volume of CSF exchanged every minute (here a constant 0.7% of the
volume of CSF/min), V is the volume of CSF, and
T is the time (min) elapsed after
administration. Considering enzymatic IL-1 degradation and binding
and uptake mechanisms, a smaller amount of IL-1 than that calculated
might be bioavailable after intracerebroventricular administration.
Therefore, the amount of IL-1 administered in the present study is
in the pathophysiological-suprapathophysiological range observed in the
CSF during infections of the CNS: for example, 40% of patients with
bacterial meningitis exhibit >10 pg IL-1/10 µl CSF, with some
patients exhibiting >20-40 pg IL-1/10 µl CSF (13).
Address for reprint requests: E. Satinoff, Dept. of Psychology, Univ. of Delaware, Newark, DE 19716-2590.
Received 8 April 1998; accepted in final form 13 August 1998.
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REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
1.
Bibby, D. C.,
and
R. F. Grimble.
Effect of age on hypothalamic prostaglandin E2 production and fever in response to tumour necrosis factor (cachectin) and endotoxin in rats.
Clin. Sci. (Colch.)
81:
313-317,
1991[Medline].
2.
Blatteis, C. M.,
and
E. Sehic.
Fever: how many circulating pyrogens signal the brain?
News Physiol. Sci.
12:
1-9,
1997.
3.
Burtis, C. A.,
and
E. R. Ashwood.
Tietz Textbook of Clinical Chemistry (2nd ed.). Philadelphia: Saunders, 1994.
4.
Catania, A.,
L. Airaghi,
P. Motta,
M. G. Manfredi,
G. Annoni,
C. Pettenati,
F. Brambilla,
and
J. M. Lipton.
Cytokine antagonists in aged subjects and their relation with cellular immunity.
J. Gerontol. A Biol. Sci. Med. Sci.
52:
B93-B97,
1997[Abstract].
5.
Cizza, G.,
A. E. Calogero,
L. S. Brady,
G. Bagdy,
E. Bergamini,
M. R. Blackman,
G. P. Chrousos,
and
P. W. Gold.
Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis with advancing age.
Endocrinology
134:
1611-1620,
1994[Abstract].
6.
Dao, T. K.,
R. C. Bell,
J. Feng,
D., M. Jameson,
and
J. M. Lipton.
C-reactive protein, leukocytes, and fever after central IL-1 and 
-MSH in aged rabbits.
Am. J. Physiol.
254 (Regulatory Integrative Comp. Physiol. 23):
R401-R409,
1988
7.
Feng, J.,
M. Price,
J. Cohen,
and
E. Satinoff.
Prostaglandin fevers in rats: regulated change in body temperature or change in regulated body temperature?
Am. J. Physiol.
257 (Regulatory Integrative Comp. Physiol. 26):
R695-R699,
1989
8.
Foster, K.,
C. Conn,
and
M. Kluger.
Fever, tumor necrosis factor, and interleukin-6 in young, mature, and aged Fischer 344 rats.
Am. J. Physiol.
262 (Regulatory Integrative Comp. Physiol. 31):
R211-R215,
1992
9.
Hatzinger, M.,
J. Reul,
R. Landgraf,
F. Holsboer,
and
I. Neumann.
Combined dexamethasone/CRH test in rats: hypothalamo-pituitary-adrenocortical system alterations in aging.
Neuroendocrinology
64:
349-356,
1996[Medline].
10.
Hoogendijk, J. E.,
E. Fliers,
D. F. Swaab,
and
R. W. Verwer.
Activation of vasopressin neurons in the human supraoptic and paraventricular nucleus in senescence and senile dementia.
J. Neurol. Sci.
69:
291-299,
1985[Medline].
11.
Kluger, M. J.
Fever revisited.
Pediatrics
90:
846-850,
1992
12.
Landgraf, R.,
I. Neumann,
F. Holsboer,
and
Q. J. Pittman.
Interleukin-1 stimulates both central and peripheral release of vasopressin and oxytocin in the rat.
Eur. J. Neurosci.
7:
592-598,
1995[Medline].
13.
López-Cortés, L. F.,
M. Cruz-Ruiz,
J. Gómez-Mateos,
D. Jiménez-Hernández,
J. Palomino,
and
E. Jiménez.
Measurement of levels of tumor necrosis factor- and interleukin-1 in the CSF of patients with meningitis of different etiologies: utility in the differential diagnosis.
Clin. Infect. Dis.
16:
534-539,
1993[Medline].
14.
Luheshi, G.,
and
N. Rothwell.
Cytokines and fever.
Int. Arch. Allergy Immunol.
109:
301-307,
1996[Medline].
15.
Martin, L. W.,
L. B. Deeter,
and
J. M. Lipton.
Acute-phase response to endogenous pyrogen in rabbit: effects of age and route of administration.
Am. J. Physiol.
257 (Regulatory Integrative Comp. Physiol. 26):
R189-R193,
1989
16.
Miller, D.,
T. Yoshikawa,
S. C. Castle,
and
D. Norman.
Effect of age on fever response to recombinant tumor necrosis factor alpha in a murine model.
J. Gerontol. A Biol. Sci. Med. Sci.
46:
M176-M179,
1991.
17.
Miller, D. J.,
T. T. Yoshikawa,
and
D. C. Norman.
Effect of age on fever response to recombinant interleukin-6 in a murine model.
J. Gerontol. A Biol. Sci. Med. Sci.
50:
M276-M279,
1995[Abstract].
18.
Norman, D. C.,
D. Grahn,
and
T. T. Yoshikawa.
Fever and aging.
J. Am. Geriatr. Soc.
33:
859-863,
1985[Medline].
19.
Norman, D. C.,
R. H. Yamamura,
and
T. T. Yoshikawa.
Fever response in old and young mice after injection of interleukin 1.
J. Gerontol. A Biol. Sci. Med. Sci.
43:
M80-M85,
1988.
20.
Plata-Salamán, C. R.,
and
S. E. Ilyin.
IL-1-induced modulation of the hypothalamic IL-1 system, TNF- and TGF-1 mRNAs in obese (fa/fa) and lean (Fa/Fa) Zucker rats: implications to IL-1 feedback systems and cytokine-cytokine interactions.
J. Neurosci. Res.
49:
541-550,
1997[Medline].
21.
Plata-Salamán, C. R.,
J. R. Vasselli,
and
G. Sonti.
Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia.
Obesity Res.
5:
36-42,
1997[Medline].
22.
Refinetti, R.,
H. Ma,
and
E. Satinoff.
Body temperature rhythms, cold tolerance, and fever in young and old rats of both genders.
Exp. Gerontol.
25:
533-543,
1990[Medline].
23.
Roubenoff, R.,
T. B. Harris,
L. W. Abad,
P. W. F. Wilson,
G. E. Dallal,
and
C. A. Dinarello.
Monocyte cytokine production in an elderly population: effect of age and inflammation.
J. Gerontol. A Biol. Sci. Med. Sci.
53A:
M20-M26,
1998[Abstract].
24.
Sapolsky, R.,
L. Krey,
and
B. McEwen.
The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis.
Endocr. Rev.
7:
284-301,
1986[Medline].
25.
Schobitz, B.,
F. Holsboer,
W. Sutanto,
G. Gross,
E. Schonbaum,
and
E. R. de Kloet.
Corticosterone modulates interleukin-evoked fever in the rat.
Neuroendocrinology
59:
387-395,
1994[Medline].
26.
Sonti, G.,
S. E. Ilyin,
and
C. R. Plata-Salamán.
Anorexia induced by cytokine interactions at pathophysiological concentrations.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R1394-R1402,
1996
27.
Strijbos, P. J.,
M. A. Horan,
F. Carey,
and
N. J. Rothwell.
Impaired febrile responses of aging mice are mediated by endogenous lipocortin-1 (annexin-1).
Am. J. Physiol.
265 (Endocrinol. Metab. 28):
E289-E297,
1993
28.
Wachulec, M.,
E. Peloso,
and
E. Satinoff.
Individual differences in response to LPS and psychological stress in aged rats.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R1252-R1257,
1997
29.
Wilkinson, M. F.,
T. F. Horn,
N. W. Kasting,
and
Q. J. Pittman.
Central interleukin-1 stimulation of vasopressin release into the rat brain: activation of an antipyretic pathway.
J. Physiol. (Lond.)
481:
641-646,
1994[Medline].
30.
Wilson, B. C.,
K. Fulop,
and
A. J. S. Summerlee.
Changing effect of i. c. v. IL-1 on vasopressin release in anaesthetized, female rats at different stages of lactation: role of prostaglandins and noradrenaline.
J. Neuroendocrinol.
8:
915-920,
1996[Medline].
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