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Experimental Physiology 91.4 pp 741-746
DOI: 10.1113/expphysiol.2006.033688
© The Physiological Society 2006
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Mifepristone (RU38486) influences the core temperature response of term pregnant rats to intraperitoneal lipopolysaccharide

Sherry L. Moore1 and James E. Fewell1

1 Department of Physiology & Biophysics, University of Calgary, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4 N1, Canada


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Pregnancy alters the cytokine, prostanoid and core temperature responses of rats to infectious stimuli at a time when blood levels of the endogenous glucocorticoid corticosterone are elevated. Given that glucocorticoids attenuate bacterial pyrogen-induced fever in rats, the present experiments were carried out to test the hypothesis that administration of RU38486, a glucocorticoid type II receptor antagonist, would restore the febrile response to E. coli lipopolysaccharide (LPS) in pregnant rats on day 21 of gestation. Pregnant rats were randomly allocated to one of four experimental groups depending upon whether they received RU38486 (20 mg kg–1 intragastric) or vehicle followed by E. coli LPS (160 µg kg–1I.P.; a minimal dose that elicits maximal febrile response in non-pregnant rats) or vehicle. Basal core temperature was not altered by intragastric administration of RU38486 or vehicle. Following intragastric administration of vehicle, intraperitoneal administration of E. coli LPS produced a significant hypothermia with latency, duration and magnitude of 0.5 h, 2 h and –1.3°C, respectively. Following intragastric administration of RU38486, however, intraperitoneal administration of E. coli LPS elicited only a minimal decrease in core temperature which was not significantly different from control values. Thus, our data provide evidence that endogenous glucocorticoids play a role in modulating the early core temperature response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.

(Received 17 February 2006; accepted after revision 26 April 2006; first published online 27 April 2006)
Corresponding author J. E. Fewell: Heritage Medical Research Building 206, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4 N1, Canada. Email: fewell{at}ucalgary.ca.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Pregnancy alters the cytokine, prostanoid and core temperature responses of rats to infectious stimuli (Simrose & Fewell, 1995; Martin et al. 1995; Stobie-Hayes & Fewell, 1996; Fewell et al. 2002; Imai-Matsumara et al. 2002; Fofie & Fewell, 2003; Fofie et al. 2005). For example, we have shown that intraperitoneal administration of E. coli lipopolysaccharide (LPS) in doses that elicit half-maximal (EC50) and maximal (EC100) febrile responses in non-pregnant rats produces a gestation- and dose-dependent hypothermia in pregnant rats (Fofie & Fewell, 2003). Furthermore, E. coli LPS elicits significant increases in plasma concentrations of interleukin(IL)-1ß, IL-6, IL-1ra and tumour necrosis factor-{alpha} (TNF{alpha}) in non-pregnant rats, whereas it elicits significant increases in IL-1ra and TNF{alpha} (i.e. antipyretic/cryogenic cytokines) but not IL-1ß and IL-6 (i.e. pyrogenic cytokines) in pregnant rats (Fofie et al. 2005). We have also shown that pregnancy impairs the synthesis and release of E-series prostaglandins into the interstitial fluid of the peri-OVLT (Organum Vasculosum Laminal Terminalis) region following systemic administration of IL-1ß (Fewell et al. 2002). The mechanisms and consequences of the unique pregnancy-induced changes in the thermoregulatory component of the acute phase response to bacterial pyrogen are presently unknown.

Numerous physiological changes occur during the maternal adaptation to pregnancy, including changes in the blood concentrations of a number of hormones (e.g. corticosterone) that may modulate the core temperature response to infectious stimuli. For example, the blood concentration of corticosterone remains relatively low until day 10 of gestation but then increases significantly, reaching a maximum at term of pregnancy (Dupouy et al. 1975; Waddell & Atkinson, 1994; Atkinson & Waddell, 1995; Smith et al. 1997); at term of gestation, blood concentrations of corticosterone average 50% higher than that observed in the non-pregnant state (Waddell & Atkinson, 1994). Given that Coelho et al. (1992) and Morrow et al. (1993) have shown that endogenous glucocorticoids modulate the core temperature response of male rats to bacterial pyrogen, it is possible that a pregnancy-induced increase in the blood concentration of corticosterone participates in mediating the altered core temperature response to bacterial pyrogen that occurs near the term of pregnancy. In the study of Morrow et al. (1993), administration of RU38486, a type II glucocorticoid receptor antagonist (Gagne et al. 1985), accentuated the core temperature response to bacterial pyrogen compared to that observed when bacterial pyrogen followed administration of vehicle. Accordingly, the present experiments have been carried out to investigate the effect of administration of RU38486 on the core temperature response to bacterial pyrogen in term pregnant rats. Specifically, experiments were carried out to test the hypothesis that administration of RU38486 would restore the febrile response to an EC100 dose of E. coli LPS in pregnant rats on day 21 of gestation.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were carried out on 34 time-mated pregnant Sprague–Dawley rats (Charles River Canada) undergoing their first pregnancy and weighing an average of 308 ± 16 g at the time of study; the day of mating was considered to be day 0 of gestation. The rats were housed individually in Plexiglass cages kept in a humidity- (30–40%) and temperature-controlled (25 ± 1°C, the selected ambient temperature and thermoneutral temperature of non-pregnant and pregnant rats; Eliason & Fewell, 1997) environmental chamber on a 12 h–12 h light–dark cycle with lights on from 07.00 h, and were handled and draped several times prior to an experiment to familiarize the animals with the investigator and experimental procedures. All animals had continuous access to food (Purina Laboratory Diet 5001) and tap water.

All surgical and experimental procedures were carried out in accordance with the Guide to the Care and Use of Experimental Animals provided by the Canadian Council on Animal Care and with the approval of the Animal Care Committee of the University of Calgary.

Surgical preparation

On day 16 of gestation, each animal was placed in a cylindrical anaesthesia chamber (Kent Scientific Corporation, Torrington, CT), and anaesthesia was rapidly induced with 2% halothane in oxygen. Anaesthesia was then maintained via mask using an open-circuit anaesthesia system delivering 2% halothane in oxygen at 1 l min–1. A paramedian laparotomy was performed utilizing aseptic technique, and a free-floating, battery-operated telemetry device (TA10TA-F20, Data Sciences International, St. Paul, MN) was placed in the peritoneal cavity for measurement of core temperature. In addition, a sterile catheter of silicone tubing (Dow Corning Silastic®; Helix Medical Inc., Carpintera, CA) was inserted into the peritoneal cavity for administration of E. coli LPS or vehicle. Intraperitoneal administration of injectate by this technique does not elicit stress-induced fever in rats as normally occurs when once pierces the abdominal wall with a needle for drug administration (Dymond & Fewell, 1998). The catheter was then tunnelled subcutaneously, exteriorized at the dorsal scapular area, and sealed with a ligature. Finally, skin was sutured to close the abdominal incision and the catheter was secured in place with a purse-string suture and tissue adhesive (VetbondTM., 3M, St. Paul, MN). Topical antibiotic (TopazoneTM., Austin, Lavaltrie, QC) and spray adhesive bandage (OpSiteTM., Smith & Nephew, St. Laurent, QC) were applied to all wounds.

Experimental protocol

Pregnant rats were studied at term of gestation (i.e. day 21) after random allocation to one of four experimental groups depending upon whether they received RU38486 or vehicle followed by E. coli LPS or vehicle. On the day before an experiment, each rat was removed from its cage and weighed. On the day of an experiment, following an acceptable control period defined as five 2 min measurements of core temperature that did not vary by more than ±0.2°C, each rat was removed from its cage and given an intragastric bolus of 20 mg kg–1 RU38486 or vehicle; the rat was then returned to its cage. After 120 min, the rat was again removed from its cage and given an intraperitoneal injection of 160 µg kg–1 E. coli or vehicle. The rat was then returned to its cage, and core temperature was measured at 2 min intervals for a period of 6 h. All experiments were carried out during the light cycle and began at ~10.00 h to avoid circadian variations in basal core temperature, blood corticosterone concentrations and possible circadian effects on the core temperature response to perturbation.

Conditions of observation

During an experiment, each animal was studied in her cage in the aforementioned environmental chamber. Each cage was placed over a platform antenna (PhysioTel CTR 86; RLA-1020 Data Sciences International, St. Paul, MN), which received the output frequency (in Hz) from the implanted telemetry device. The platform antenna was interfaced with a peripheral processor for determination of core temperature.

Oral and intraperitoneal administration of drugs

All animals received an intragastric injection of the glucocorticoid antagonist RU38486 (Mifepristone, Sigma) suspended in sterile corn oil (20 mg ml–1) or an equal volume of vehicle (sterile corn oil). The suspension was achieved by rapidly stirring the mixture warmed to 37°C with a magnetic spin bar on a dual hot plate–magnetic stirrer (VWR 320). The dose of RU38486 was chosen based upon the results of Morrow et al. (1993), who showed that 20 mg kg–1 of RU38486 accentuates the febrile response to E. coli LPS in male rats. Following intragastric administration, RU38486 is readily absorbed and reaches peak levels in plasma within 60–90 min (Deraedt et al. 2003). Furthermore, uptake of RU38486 into tissues is great, as tissue concentrations rise rapidly above that of plasma. Relative to other endogenous or synthetic glucocorticoids, RU38486 displays both a strong binding affinity for and a slow dissociation rate from the intracellular glucocorticoid receptor (Philibert, 1984).

For intragastric delivery of RU38486 or vehicle, an 18 gauge and 7.6 cm long curved intubation needle (Popper & Sons, New Hyde Park, NY) was connected to a 1 ml syringe, into which the prepared injectate was drawn. Each animal was removed from its cage and draped, and the skin at the nape of the neck was delicately pinched to extend the head of the animal and align the mouth, throat and oesophagus. The ball of the intubation needle was then placed near the back of the throat, slightly off to the side, and passed down the oesophagus as the animal swallowed. Once the needle was fully inserted, the injectate was plunged into the stomach; the needle was then was carefully removed.

All animals then received an intraperitoneal injection of either E. coli LPS (E. coli 0111:B4, Sigma) dissolved in sterile saline or an equal volume of vehicle (sterile saline) as previously described (Fofie & Fewell, 2003). We have previously shown that 160 µg kg–1 E. coli LPS is the EC100, in that it is the smallest dose that elicits a maximal febrile response in non-pregnant rats (Fofie & Fewell, 2003).

Statistical analysis

Statistical analysis was carried out using a two-factor analysis of variance for repeated measures followed by a Newman–Keuls multiple comparison test to determine whether injectate or time influenced core temperature. In addition, a two-factor analysis of variance followed by a Newman–Keuls multiple comparison test was done to determine whether injectate or time influenced the change in core temperature from control values. All results are reported as means ± 1 S.D.; P < 0.05 was considered to be of statistical significance.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Basal core temperature was similar in the various experimental groups (i.e. vehicle–vehicle, 36.4 ± 0.2°C; vehicle–LPS, 36.4 ± 0.2°C; RU38486–vehicle, 36.5 ±0.2°C; and RU38486–LPS, 36.6 ± 0.2°C; n.s.) and was not altered by intragastric administration of vehicle or RU38486. Following intragastric administration of vehicle, intraperitoneal administration of E. coli LPS produced a significant hypothermia with latency, duration and magnitude of 0.5 h, 2 h and –1.3°C, respectively. Following intragastric administration of RU38486, however, intraperitoneal administration of E. coli LPS elicited a small decrease in core temperature of –0.4°C which was not significantly different from control core temperature. Intraperitoneal administration of vehicle following intragastric administration of either vehicle or RU38486 elicited only minimal changes in core temperature from control values. The change in core temperature from control values that was observed following intragastric administration of vehicle and intraperitoneal administration of E. coli LPS was significantly greater than that observed in the other three experimental groups (Fig. 1). A modest increase in core temperature was observed in all groups towards the end of the experiment (the change in core temperature from control values was not different among groups), probably as a result of the normal circadian variation in basal core temperature.


Figure 1
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  		Figure 1.  Change in core temperature from control values after intraperitoneal administration of vehicle or 160 µg kg–1E.coli LPS following intragastric administration of vehicle or RU38486
Data are means ± S.D. *P < 0.05 versus vehicle–vehicle, RU38486–vehicle and RU38486–LPS at same time point by ANOVA and Newman–Keuls multiple comparison test

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our experiments provide new information about possible mechanisms of the unique thermoregulatory response observed in term pregnant rats following intraperitoneal administration of bacterial pyrogen. A novel finding in our study was that although intragastric administration of RU38486 did not alter basal core temperature in term pregnant rats, it significantly attenuated the hypothermic response observed following intraperitoneal administration of 160 µg kg–1 E. coli LPS. Thus, our data provide evidence that endogenous glucocorticoids play a role in modulating the early core temperature response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.

In male and non-pregnant female rats, systemic administration of infectious stimuli such as exogenous (e.g. LPS) or endogenous pyrogen (e.g. IL-1) elicits fever and activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the secretion of corticosterone which acts via a negative feedback mechanism to modulate the core temperature response and plays a role in ensuring survival (Besedovsky et al. 1975, 1986; Coelho et al. 1992; Morrow et al. 1993; Brunton et al. 2005). Systemic administration of IL-1ß increases corticotrophin releasing hormone via prostaglandin-dependent activation of brainstem noradrenergic neurones, which project to corticotrophin-releasing hormone neurones in the paraventricular nucleus. It also leads to secretion of adrenocorcorticotrophic hormone and corticosterone, which in turn has multiple effects on the cascade of events that mediate the febrile response (Beutler & Cerami, 1986; Kakucska et al. 1993; Ericsson et al. 1994, 1995; Givalois et al. 1995; Turnbull et al. 1998; Zhang & Rivest, 1999; Rivest et al. 2000; Buller et al. 2001). For example, glucocorticoids inhibit the production and action of immunoregulatory cytokines such as IL-1, suppress the induction of cytosolic phospholipase A2 and cyclo-oxgenase-2 mRNA, and they block the production of prostaglandins, which play an important role in orchestrating central nervous system mechanisms to effect the core temperature response following systemic administration of bacterial or endogenous pyrogen (Milton & Wendlandt, 1970; Hirata et al. 1980; Snyder & Unanue, 1982; Newton et al. 1997).

In near-term pregnant rats, however, exposure to non-infectious (e.g. forced swimming or exposure to an elevated plus maze) or infectious stimuli (e.g. LPS or IL-1ß) elicits a minimal glucocorticoid response because the responsiveness of the HPA axis is markedly attenuated compared to that observed in non-pregnant rats (Neumann et al. 1998; Johnstone et al. 2000; Brunton et al. 2005). For example, Brunton et al. (2005) have shown that systemic administration of a small dose of IL-1ß (i.e. 500 ng kg–1) elicits a prompt adrenocorcorticotrophic hormone and corticosterone response in non-pregnant rats but not in pregnant rats; in pregnant rats, plasma levels of these hormones were not significantly different from control levels following systemic administration of IL-1ß. The hyporesponsiveness of the HPA axis to these stressors is probably mediated through an opioid mechanism acting at the level of the paraventricular nucleus corticotrophin-releasing hormone neurones (Brunton et al. 2005).

Thus, although it is unlikely that corticosterone modulates the core temperature response to infectious stimuli in pregnant rats as in non-pregnant rats via a negative feedback mechanism involving the HPA axis, it is possible that the elevated basal corticosterone levels observed near the term of pregnancy modulate the core temperature response via a feedforward mechanism which serves to inhibit pyrogenic cytokine production and prostaglandin synthesis and secretion upon exposure to infectious stimuli. In support of this postulate, we have recently shown that pregnancy alters the balance of pyrogenic cytokines and antipyretic cytokines in response to bacterial pyrogen (Fofie et al. 2005). Specifically, we found that E. coli LPS elicits statistically significant increases in plasma concentrations of IL-1ß, IL-6, IL-1ra and TNF{alpha} in non-pregnant rats compared to that observed following vehicle. In pregnant rats, however, E. coli LPS elicits statistically significant increases in antipyretic cytokines (i.e. IL-1ra and TNF{alpha}) but not in pyrogenic cytokines (i.e. IL-1ß and IL-6). Furthermore, we have shown that pregnancy impairs the synthesis and release of E-series prostaglandins into the interstitial fluid of the peri-OVLT region following systemic administration of IL-1ß (Fewell et al. 2002).

There are other possible although unlikely explanations for the effects of RU38486 on the core temperature response to LPS in term pregnant rats as observed in our present experiments. RU38486 (Mifepristone), a progesterone antagonist, was used in our experiments because of its potent antiglucocorticoid activity. Relative to other endogenous or synthetic glucocorticoids, RU38486 displays both a strong binding affinity for and a slow dissociation rate from the intracellular glucocorticoid receptor (Philibert, 1984). Although progesterone has thermogenic action in rats (i.e. it increases core temperature), probably via its action on preoptic thermosensitive neurones, it does not appear to influence basal core temperature at term of pregnancy, since basal core temperature was unchanged following administration of RU38483 (Freeman et al. 1970; Nakayama et al. 1975). Furthermore, it is unlikely that progesterone played a role in the core temperature response to bacterial pyrogen, since administration of RU38483 significantly attenuated rather than accentuated the hypothermic response to E. coli LPS. At term of pregnancy, blood concentrations of corticosterone are relatively high and blood concentrations of progesterone are relatively low in rats (Morishige et al. 1973; Pepe & Rothchild, 1974).

Hardwick et al. (1989) have shown that RU38486 has thermogenic effects, probably secondary to a stimulated corticotrophin-releasing hormone-mediated sympathetic activation of brown adipose tissue. In their experiments, subcutaneous injection of 10 mg kg–1 RU38486 produced a small, ~1.5 ml min–1 kg–0.75, but statistically significant increase in oxygen consumption which peaked at 60–80 min; core temperature was not measured in their experiments. As previously mentioned, basal core temperature was unchanged in our experiments following administration of RU38486, so it is unlikely that a similar mechanism participated in modulating the thermogenic response to LPS following RU38486.

In summary, our present experiments provide evidence that endogenous glucocorticoids play a role in modulating the early hypothermic response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Atkinson HC & Waddell BJ (1995). The hypothalamic-pituitary-adrenal axis in rat pregnancy and lactation: circadian variation and interrelationship of plasma adrenocorticotropin and corticosterone. Endocrinology 136, 512–520.[Abstract]

Besedovsky H, Del Rey A, Sorkin E & Dinarello CA (1986). Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233, 652–654.[Abstract/Free Full Text]

Besedovsky H, Sorkin E, Keller M & Muller J (1975). Changes in blood hormone levels during the immune response. Proc Soc Exp Biol Med 150, 466–470.[Abstract]

Beutler B & Cerami A (1986). Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 320, 584–588.[CrossRef][Medline]

Brunton PJ, Meddle SL, Ma S, Ochedalski T, Douglas AJ & Russell JA (2005). Endogenous opioids and attenuated hypothalamic-pituitary-adrenal axis responses to immune challenge in pregnant rats. J Neurosci 25, 5117–5126.[Abstract/Free Full Text]

Buller KM, Xu Y, Dayas CV & Day TA (2001). Dorsal and ventral medullary catecholamine cell groups contribute differentially to systemic interleukin-1ß-induced HPA axis responses. Neuroendocrinology 73, 129–138.[CrossRef][Medline]

Coelho MM, Souza GEP & Pela IR (1992). Endotoxin-induced fever is modulated by endogenous glucocorticoids in rats. Am J Physiol 263, R423–R427.[Medline]

Deraedt R, Bonnat C, Busigny M, Chatelet P, Cousty C, Mouren M, Philibert D, Pottier J & Salmon J (2003). Pharmacokinetics of RU 486. In The Antiprogestin Steroid RU 486 and Human Fertility Control, ed. Baulieu EE & Segal SJ, pp. 103–122. Plenum, New York.

Dupouy JP, Coffigny H & Magre S (1975). Maternal and fetal corticosterone levels during late pregnancy in rats. J Endocrinol 65, 347–352.[Abstract]

Dymond KE & Fewell JE (1998). Coordination of autonomic and behavioral thermoregulatory responses during exposure to a novel stimulus in rats. Am J Physiol 275, R673–R676.[Medline]

Eliason HL & Fewell JE (1997). Thermoregulatory control during pregnancy and lactation in rats. J Appl Physiol 83, 837–844.[Abstract/Free Full Text]

Ericsson A, Kovacs KJ & Sawchenko PE (1994). A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J Neurosci 14, 897–913.[Abstract]

Ericsson A, Liu C, Hart RP & Sawchenko PE (1995). Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol 361, 681–698.[CrossRef][Medline]

Fewell JE, Eliason HL & Auer RN (2002). Peri-OVLT E-series prostaglandins and core temperature do not increase following intravenous IL-1ß in pregnant rats. J Appl Physiol 93, 531–536.[Abstract/Free Full Text]

Fofie AE & Fewell JE (2003). Influence of pregnancy on plasma cytokines and the febrile response to intraperitoneal administration of bacterial endotoxin in rats. Exp Physiol 88, 747–754.[Abstract]

Fofie AE, Fewell JE & Moore SL (2005). Pregnancy influences the plasma cytokine response to intraperitoneal administration of bacterial endotoxin in rats. Exp Physiol 90, 95–101.[Abstract/Free Full Text]

Freeman ME, Crissman JK, Louw GN, Butcher RL & Inskeep EK (1970). Thermogenic action of progesterone in the rat. Endocrinology 86, 717–720.[Medline]

Gagne D, Pons M & Philibert D (1985). RU 38486: a potent antiglucocorticoid in vitro and in vivo. J Steroid Biochem 23, 247–251.[CrossRef][Medline]

Givalois L, Siaud P, Mekaouche M, Ixart G, Malaval F, Assenmacher I & Barbanel G (1995). Early hypothalamic activation of combined Fos and CRH41 immunoreactivity and of CRH41 release in push-pull cannulated rats after systemic endotoxin challenge. Mol Cel Neuropathol 26, 171–186.

Hardwick AJ, Linton EA & Rothwell NJ (1989). Thermogenic effects of the antiglucorticoid RU-486 in the rat: involvement of corticotrophin-releasing factor and sympathetic activation of brown adipose tissue. Endocrinology 124, 1684–1688.[Abstract]

Hirata F, Schiffmann E, Venkatasubramanian K, Salomon D & Axelrod J (1980). A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci U S A 77, 2533–2536.[Abstract/Free Full Text]

Imai-Matsumara K, Matsumura K, Terao A & Watanabe Y (2002). Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2. Am J Physiol Regul Integr Comp Physiol 283, R1346–R1353.[Abstract/Free Full Text]

Johnstone HA, Wigger A, Douglas AJ, Neumann ID, Landgraf R, Seckl JR & Russell JA (2000). Attenuation of hypothlamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms. J Neuroendocrinol 12, 811–822.[CrossRef][Medline]

Kakucska I, Qi Y, Clark BD & Lechan RM (1993). Endotoxin-induced corticotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is mediated centrally by interleukin-1. Endocrinology 133, 815–821.[Abstract]

Martin SM, Malkinson TJ, Veale WL & Pittman QJ (1995). Fever in pregnant, parturient, and lactating rats. Am J Physiol 268, R919–R923.[Medline]

Milton AS & Wendlandt S (1970). A possible role for prostaglandin E1 as a modulator for temperature regulation in the central nervous system of the cat. J Physiol 207, 76P–77P.

Morishige WK, Pepe GJ & Rothchild I (1973). Serum luteinizing hormone, prolactin and progesterone levels during pregnancy in the rat. Endocrinology 92, 1527–1530.[Medline]

Morrow LE, McClellan JL, Conn CA & Kluger MJ (1993). Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. Am J Physiol 264, R1010–R1016.[Medline]

Nakayama T, Suzuki M & Ishizuka N (1975). Action of progesterone on preoptic thermosensitive neurones. Nature 258, 80.[Medline]

Neumann ID, Johnstone HA, Hatzinger M, Liebsch G, Shipston M, Russell JA, Landgraf R & Douglas AJ (1998). Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes. J Physiol 508, 289–300.[Abstract/Free Full Text]

Newton R, Kuitert LM, Slater DM, Adcock IM & Barnes PJ (1997). Cytokine induction of cytosolic phospholipase A2 and cyclooxygenase-2 mRNA is suppressed by glucocorticoids in human epithelial cells. Life Sci 60, 67–78.[CrossRef][Medline]

Pepe GJ & Rothchild I (1974). A comparative study of serum progesterone levels in pregnancy and various types of pseudopregnancy in the rat. Endocrinology 95, 275–279.[Medline]

Philibert D (1984). RU38486: an original multifaceted antihormone in vivo. In Adrenal Steroid Antagonism, ed. Agarwal MJ, pp. 77–101. Gruyer, Berlin.

Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J & Laflamme N (2000). How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Exp Biol Med 223, 22–38.[Abstract/Free Full Text]

Simrose RL & Fewell JE (1995). Body temperature response to IL-1ß in pregnant rats. Am J Physiol 38, R1179–R1182.

Smith FG, Fewell JE & Abu-Amarah I (1997). Endocrine effects of pregnancy and exposure to a simulated open field in rats. Am J Physiol 273, R1053–R1057.[Medline]

Snyder DS & Unanue ER (1982). Corticosteroids inhibit murine macrophage 1a expression and interleukin 1 production. J Immunol 129, 1803–1805.[Abstract]

Stobie-Hayes KM & Fewell JE (1996). Influence of pregnancy on the febrile response to intracerebroventricular administration of PGE1 in rats. J Appl Physiol 81, 1312–1315.[Abstract/Free Full Text]

Turnbull AV, Lee S & Rivier C (1998). Mechanisms of hypothalamic-pituitary-adrenal axis stimulation by immune signals in the adult rat. Ann N Y Acad Sci 840, 434–443.[Abstract/Free Full Text]

Waddell BJ & Atkinson HC (1994). Production rate, metabolic clearance rate and uterine extraction of corticosterone during rat pregnancy. J Endocrinol 143, 183–190.[Abstract]

Zhang J & Rivest S (1999). Distribution, regulation and colocalization of the genes encoding the EP2- and EP4-PGE2 receptors in the rat brain and neuronal responses to systemic inflammation. Eur J Neurosci 11, 2651–2688.[CrossRef][Medline]


   Acknowledgements
 
This study was supported by the Canadian Institutes of Health Research.





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