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Endocrinology Vol. 140, No. 6 2843-2849
Copyright © 1999 by The Endocrine Society

ARTICLES

Nonresponsiveness of the Rat Hypothalamo-Pituitary-Adrenocortical Axis to Parturition-Related Events: Inhibitory Action of Endogenous Opioids1

A. Wigger, P. Lörscher, I. Oehler, M. E. Keck, T. Naruo and I. D. Neumann

Max Planck Institute of Psychiatry, D 80804 Munich, Germany

Address all correspondence and requests for reprints to: Inga D. Neumann, Max Planck Institute of Psychiatry, Kraepelinstr. 2, D 80804 Munich, Germany. E-mail: ineu{at}mpipsykl.mpg.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
During the last 2 days of pregnancy in rats, basal corticosterone secretion is enhanced, although the response of the hypothalamo-pituitary-adrenocortical (HPA) axis to emotional and physical stressors is blunted, independent of the action of endogenous opioids. In this study, alterations in the reactivity of the HPA axis, which may accompany parturition-related stimuli, and the involvement of endogenous opioids were examined in chronically catheterized rats.

In vehicle-treated controls (n = 9), ACTH and corticosterone secretion decreased in preparation for birth (P < 0.01) and further declined immediately after delivery of the second pup (P < 0.01), remaining low for 150 min. In contrast, in animals injected with the opiate antagonist naloxone (5 mg ml-1 kg-1, iv, n = 6) after delivery of the second pup, ACTH and corticosterone release were enhanced within 20 min (ACTH, 5.0-fold; corticosterone, 2.3-fold; P < 0.01 vs. controls) and returned to control levels after 90 min. In confirmation of previous reports, oxytocin secretion into blood was elevated in control rats after the onset of parturition (P < 0.01) and was further enhanced in the naloxone group (1.4-fold, P < 0.01 vs. control). Plasma lactate concentration was increased, 30 min after the onset of delivery (1.9-fold, P < 0.01), independent of the treatment. The data indicate that parturition-related events do not trigger HPA axis hormone release because of an effective inhibition by endogenous opioids. This nonresponsiveness of the HPA axis is likely to protect the pups’ well-being during birth.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN THE PERIPARTUM period, including the last days of pregnancy and lactation, functional adaptations of the hypothalamo-pituitary-adrenocortical (HPA) axis are well-established phenomena, studied not only in the rat (1, 2, 3, 4, 5) but also in sheep (for review, see Ref. 6), baboons (7), and humans (8, 9). Thus, in addition to basal hypercortisolism, an attenuated responsiveness of the HPA axis to emotional and physical stressors has been described in both pregnant (5) and lactating rats (2). Such alterations, which are likely to be induced by profound changes in the levels of circulating sexual steroids at the end of pregnancy, are manifested at various regulatory levels of the HPA axis [including, for instance, glucocorticoid feedback mechanisms (10), synthetic activity of hypothalamic CRH neurons (11), and CRH binding and CRH responsiveness of pituitary corticotrope cells (5), among others (12, 13)]. The reduced responsiveness of the HPA axis to external stimuli at the end of pregnancy is not caused by inhibition by endogenous opioids; but rather, the excitatory effect of endogenous opioids on corticotropin (ACTH) secretion, as found in virgin rats, disappears at the end of pregnancy (4). Furthermore, functional and morphological adaptations of the hypothalamo-neurohypophysial system [in particular, the oxytocinergic (OXT) system] have been extensively described in the peripartum period (14, 15, 16, 17, 18). For example, with the progression of pregnancy (19) [and in particular, during the parturition progress (20)], OXT cells are effectively inhibited by endogenous opioids, which prevents premature OXT secretion from the posterior pituitary where it is stored.

In contrast to the OXT system (21), the activity of the HPA axis during parturition has not been previously monitored in the rat. In several species (including sheep, pigs, and humans), an increase in maternal ACTH and/or cortisol has been reported on the day of parturition (8, 22, 23, 24, 25, 26). In humans, an enhanced HPA axis secretory activity has been found during the dilatation and expulsion stages (8, 27, 28); whereas in the pig, neither vaginal cervical dilatation nor external events, e.g. space restriction of the gilt, induced cortisol secretion (29).

The aim of the present study was to investigate alterations in HPA axis activity during parturition in the rat. The parturition process, with the delivery of 12–15 pups, lasts about 90 min and is characterized by significant behavioral activation of the dam. This includes nest-building before and during ongoing parturition, the typical crouching position during each period of labor before the expulsion of the pup, pulling and intense licking of the expelled pup, placentophagia, and grooming (30). To monitor ACTH and corticosterone secretory responses accompanying these parturition-related behaviors, rats were implanted with chronic jugular vein catheters. Further, as the plasma levels of endogenous opioids increase during parturition (28, 31) and exert an inhibitory action on the OXT system (20, 32), the involvement of endogenous opioid action on the HPA axis activity was assessed by administration of the opioid antagonist naloxone (NLX).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the Government of Bavaria, Germany.

Virgin female Wistar rats (260–290 g BW, Charles River Laboratories, Inc., Sulzfeld, Germany) were mated overnight with sexually experienced males. Mating was confirmed by the presence of vaginal plugs on the following morning (day 1 of pregnancy). Pregnant rats were housed three per cage and were maintained under standard laboratory conditions (12-h light, 12-h dark cycle, lights on at 0700 h; at 22 C, 60% humidity; with food and water ad libitum) until day 17 of pregnancy.

Surgery for blood sampling
On day 17 of pregnancy, rats (290 ± 7.60 g BW) were implanted with a chronic jugular vein catheter, under halothane anesthesia, using sterile procedures. The jugular vein was exposed; and a silicone tubing catheter (id, 0.635 mm; od, 1.194 mm; Dow Corning Corp., Midland, MI), connected to a PE-50 polyethylene tubing, was inserted approximately 3 cm into the vessel, until the tip reached the right atrium. Then, the catheter was fixed at the vessel and exteriorized dorsally in the cervical region. The catheter was filled with gentamicin-solution (30,000 IU/ml; Gentacur, Centravet, Bad Beutheim, Germany; in sterile 0.9% saline) and flushed with 0.2 ml of the same solution after 3 days. After surgery, rats were housed singly in experimental cages (20 x 30 cm floor with 40-cm high plexiglass sidewalls), allowing subsequent blood sampling from and intensive observation of the freely moving animals, during the experiment, without additional disturbances.

Experimental protocol
Behavioral and endocrine responses during parturition. As described in detail in Fig. 1Go, at 0800 h of the first expected day of parturition, i.e. day 22 of pregnancy, and 5 days after surgery, the jugular vein catheter was attached to an extension tubing connected to a 1-ml plastic syringe filled with sterile heparinized 0.9% saline (30 IU/ml, Heparin-Natrium, Ratiopharm, Ulm, Germany), and the rats (355 ± 8.23 g BW) were left undisturbed for 90 min. For detection of basal plasma hormone concentrations, 0.6-ml (for OXT, ACTH, and corticosterone), 0.3-ml (for ACTH, corticosterone, and lactate), or 0.2-ml (for ACTH and corticosterone) blood samples, replaced immediately by sterile 0.9% saline, were collected in 1.5-h (ACTH, corticosterone) or 3-h (OXT, lactate) intervals between 0930 h and 2000 h or until onset of parturition (Fig. 1Go). Immediately after delivery of the second pup, a 0.6-ml blood sample was taken; and then NLX (5 mg ml-1 kg-1 BW, n = 6) or vehicle (sterile saline, 1 ml kg-1 BW, n = 9) was injected iv. During the following 60 min, consecutive blood samples were collected in 10-min (ACTH, corticosterone) or 20-min (OXT) intervals. In addition, the plasma lactate concentration was estimated, 30 min after delivery of the second pup. Further blood samples (ACTH, corticosterone) were collected in 30-min intervals between 60 and 150 min after delivery of the second pup. To avoid hemorrhage-induced effects, 1 ml of blood, sampled from donor rats, was slowly infused (over 3 min) to the pregnant and parturient rats, respectively, in 3-h intervals before parturition and immediately after blood sampling at 60 min after delivery of the second pup.



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  		Figure 1. Timepoints and volumes of blood sampling before and during parturition. Plasma concentrations of either ACTH (A), corticosterone (B), oxytocin (OXT), or lactate (L) were estimated at the indicated timepoints. The diamonds indicate the approximate onset times of parturition (delivery of the second pup) in rats treated with either vehicle (C) or NLX (N) on day 22 (white diamonds) and day 23 (black diamonds) of pregnancy.

 
During parturition, animals were continuously observed for 60 min, and the following parameters were recorded: 1) onset of labor; 2) time of delivery of each pup; and 3) occurrence of maternal behavior, including placentophagia, licking, and grouping of the pups.

Females that did not deliver on day 22 of pregnancy were disconnected from the extension tubing at 2130 h and reattached on the next day at 0800 h, followed by the same protocol as the day before.

On postpartum day 1, the number of live pups of each dam was counted to monitor the survival of the offspring. Then the dams and their offspring were killed by an overdose of halothane.

RIAs for ACTH, corticosterone, OXT, and lactate measurement. All blood samples were collected on ice in EDTA-coated tubes containing 10 µl aprotinin (Trasylol, Bayer AG, Leverkusen, Germany) and centrifuged at 4 C (5000 rpm, 5 min). Plasma aliquots were stored at -80 C (80 µl for ACTH) or -20 C (200 µl for OXT, 30 µl for corticosterone, 50 µl for lactate) until assay.

ACTH and corticosterone plasma concentrations were estimated using commercially available RIA kits (ACTH: Biochem Immunosystems, Freiburg, Germany, sensitivity < 1.0 pg/ml; corticosterone: DRG-Instruments, Marburg, Germany, sensitivity < 2.0 ng/ml). The intra- and interassay coefficients of variation were <7 and 10%, respectively.

Plasma OXT was measured after extraction (by heat-activated SiO2-powder, LiChroprep Si 60, Merck KhaA, Darmstadt, Germany; for a more detailed description, see Ref. 33) using a highly sensitive and selective RIA (detection limit: 0.1 pg/sample, cross-reactivity of the antisera with other related peptides, including vasopressin, was <0.7%; for more details, see Ref. 34).

Plasma lactate concentrations were measured enzymatically (MPRI Lactate, Boehringer Mannheim, Mannheim, Germany).

Statistical analysis
Data are presented as group means ± SEM. Statistical comparisons were performed by means of statistical software (GB-Stat V6.0, Dynamic Microsystems USA). Animals with abnormal deliveries, i.e. prolonged periods of labor (n = 2), were excluded from the statistical analysis.

For the analysis of parturition-induced effects in control animals, a one-way (factor time) ANOVA for repeated measures was performed. For the comparison of parturition-induced effects in control and NLX-treated animals, a two-way (factors treatment x time) ANOVA for repeated measures was used. In addition, a one-way (factor time) ANOVA for repeated measures was performed for comparing the mean plasma levels of ACTH and corticosterone under basal conditions with those after delivery of the second pup and before drug treatment (both groups, n = 15). ANOVA tests were followed by a Newman-Keuls post hoc test, and P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
HPA axis activity before and during parturition, effects of NLX
In day-22 pregnant rats, which delivered on day 23 of pregnancy, there was a circadian rhythm of the HPA axis activity, in that plasma concentrations of ACTH and corticosterone were low between 0930 h and 1400 h and increased steadily from 1530 h until the end of the blood sampling period at 2000 h (Fig. 2Go). In contrast, on the day of parturition, either in rats delivering on day 22 or day 23 of pregnancy, there were no circadian changes in plasma ACTH and corticosterone, in that the preparturition levels of both hormones were at the level of the nocturnal peak, even between 0930 h and 1400 h (Fig. 2Go).



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  		Figure 2. Circadian rhythm of basal plasma ACTH (A) and corticosterone (B) concentrations of pregnant rats between 0930 h and 2000 h on the day before (i.e. on day 22 of pregnancy, full lines, n = 5) and on the day of parturition (dotted lines, number of animals stated inside the diamonds). Data are the means ± SEM.

 
The comparison of pretreatment levels of ACTH (1-way ANOVA, factor time: F = 61.3, P < 0.0001) and corticosterone (factor time: F = 71.1, P < 0.0001) revealed a decline in basal levels of ACTH and corticosterone within the last 4–5 h before delivery of the first pup (n = 15, both hormones: P < 0.01 basal-3 vs. last basal; Fig. 3Go). The onset of delivery induced a further decrease in ACTH and corticosterone release, because plasma hormone concentrations were significantly lower after delivery of the second pup, compared with those in the last basal sample (n = 15, both hormones: P < 0.01; Fig. 3Go).



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  		Figure 3. Plasma ACTH (A) and corticosterone (B) concentrations up to 5 h before and during parturition. After delivery of the second pup and blood sampling, rats were injected with either vehicle (sterile saline, 1 ml kg-1, iv) or NLX (5 mg ml-1 kg-1, iv). ++, P < 0.01 vs. basal-3; ##, P < 0.01 vs. last basal (1-way ANOVA for repeated measures, followed by Newman-Keuls post hoc test); **, P < 0.01 vs. vehicle-treated control (2-way ANOVA for repeated measures, followed by Newman-Keuls post hoc test). Data are the means + SEM.

 
In vehicle-treated parturient rats, the plasma ACTH (factor time: F = 100.5, P < 0.0001) and corticosterone (factor time: F = 108.2, P < 0.0001) concentrations remained at a low level until the end of the sampling period (n = 9, both hormones: P < 0.01 during parturition vs. basal-3, basal-2 and last basal; Fig. 3Go). The suppression of HPA axis secretory activity during parturition occurred independently of the time of day of the births (Fig. 4Go) and (as shown in a single representative animal) the number of delivered pups within the blood sampling intervals (Fig. 5AGo).



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  		Figure 4. Plasma ACTH concentrations immediately before (last basal) and during parturition in rats delivering between 0900 h and 1400 h (filled symbols) or between 1400 h and 2130 h (empty symbols). After delivery of the second pup and blood sampling, rats were injected with either vehicle (sterile saline, 1 ml kg-1, iv, dotted lines) or NLX (5 mg ml-1 kg-1, iv, full lines). Data are the means + SEM.

 


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  		Figure 5. Representative examples for ACTH secretion, in relation to the number of delivered pups. Each delivery is indicated by an arrowhead in rats treated with either (A) vehicle (sterile saline, 1 ml kg-1, iv) or (B) NLX (5 mg ml-1 kg-1, iv). C and D represent plasma ACTH concentrations in two rats with severe aberrations in the process of delivery. In more detail, signs of strong labor were seen in one of the rats (C) for 180 min, before delivery of the first pup, and in the other rat (D) for 63 min, between delivery of the first and the second pup.

 
The statistical comparison of the HPA axis secretory responses in vehicle- and NLX-treated rats during parturition revealed significant differences (2-way ANOVA, factors treatment x time: ACTH: F = 6.87, P < 0.0001; corticosterone: F = 4.31, P < 0.0001). In NLX-treated rats, plasma concentration of ACTH significantly increased 20 min after delivery of the second pup and NLX application and remained at a significantly higher level, compared with the vehicle-treated controls, within the next 50 min (P < 0.01 vs. vehicle-treated control; Fig. 3AGo). Similarly, corticosterone secretion was elevated from 10–50 min after NLX (P < 0.01 vs. vehicle-treated control, Fig. 3BGo). By 90 min after treatment, in most cases after the last pup had been delivered, plasma concentrations of both hormones returned to control levels. Also the NLX-induced increase in HPA axis secretory activity was independent of the time of day (Fig. 4Go) and (as shown in a single representative animal) the number of delivered pups within the blood sampling intervals (Fig. 5BGo).

Two of the delivering rats showed severe aberrations in the process of delivery and were, therefore, excluded from the statistical analysis. In detail, both rats had prolonged periods of labor, either before delivery of the first pup (3 h labor, Fig. 5CGo) or between the first and the second pup (1 h labor, Fig. 5DGo). In contrast to the suppression of the HPA axis activity with the onset of delivery described above, these aberrations were accompanied by an increase in ACTH secretion until delivery of the second pup, before drug infusion. Since both rats were injected with NLX after delivery of the second pup, the further dynamics of HPA axis activity in these rats could not have been monitored under control conditions.

OXT secretion before and during parturition, effects of NLX
In day-22 pregnant rats, which delivered on day 23 of pregnancy (n = 5), there was no circadian rhythm of OXT secretion, because plasma OXT levels were similar at 0930 h (11.0 ± 1.11 pg/ml), at 1230 h (13.2 ± 1.56 pg/ml), at 1530 h (11.7 ± 0.88 pg/ml), and at 1830 h (11.7 ± 1.22 pg/ml). On the day of parturition, there were no changes in basal, preparturition plasma OXT levels related to the time of day (0930 h–1230 h: between 7.50 and 15.5 pg/ml; 1530 h–1830 h: between 7.50 and 12.5 pg/ml).

In vehicle-treated rats, OXT release was significantly enhanced after onset of parturition (P < 0.01 vs. basal), i.e. after delivery of the first two pups (1-way ANOVA, factor time: F = 126, P < 0.0001, Fig. 6Go) and remained high until 60 min after the delivery of the second pup. The parturition-related increase in OXT secretion was independent of the time of day and the number of pups delivered within the blood sampling intervals (data not shown).



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  		Figure 6. Plasma OXT concentrations during parturition in rats, treated with either vehicle (sterile saline, 1 ml kg-1, iv) or NLX (5 mg ml-1 kg-1, iv) after delivery of the second pup. ++, P < 0.01 vs. basal (1-way ANOVA for repeated measures, followed by Newman-Keuls post hoc test); **, P < 0.01 vs. respective control (2-way ANOVA for repeated measures, followed by Newman-Keuls post hoc test). Data are the means + SEM.

 
The statistical comparison of plasma OXT levels between vehicle- and NLX-treated animals during parturition revealed significant differences (2-way ANOVA, factors treatment x time: F = 4.79, P < 0.001). After NLX treatment, OXT release was further elevated (1.4-fold vs. vehicle-treated control at time point + 20; P < 0.01) and remained high until 60 min after delivery of the second pup (Fig. 6Go).

Plasma lactate levels before and during parturition, effects of NLX
The plasma lactate concentrations in both vehicle- and NLX-treated animals under basal conditions (vehicle: 0.82 ± 0.12, NLX: 1.01 ± 0.10 mmol/liter) and 30 min after delivery of the second pup (vehicle: 1.84 ± 0.43, NLX: 1.46 ± 0.27 mmol/liter) were compared with a 2-way ANOVA (factor treatment: F = 0.10, P = 0.757; factor time: F = 7.12, P = 0.021; interaction: F = 1.055, P = 0.33), indicating that the rise in plasma lactate levels was independent of the treatment. Summarized from both groups (n = 15, 1-way ANOVA, factor time: F = 10.62, P = 0.0098), plasma lactate concentrations were found to be significantly higher 30 min after delivery of the second pup (1.68 ± 0.27 mmol/liter), compared with basal conditions (0.90 ± 0.08 mmol/liter; P < 0.01).

Effect of NLX on the process of parturition and performance of maternal behavior
In our study, NLX did not affect the timing of the parturition process, because the interbirth intervals were not different between vehicle- and NLX-treated rats (Fig. 7Go). In addition, the performance of maternal behavior (including placentophagia, licking, and grouping of the pups) was not altered after NLX treatment (data not shown). The proportion of pups surviving, which was assessed on the day after parturition, was similar in the vehicle (93%)- and NLX (90%)-treated groups.



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  		Figure 7. Interbirth intervals were not different between parturient rats injected with either vehicle (sterile saline, 1 ml kg-1, iv) or NLX (5 mg ml-1 kg-1, iv). For details, see Fig. 3Go legend. Data are the means ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, for the first time, ACTH and corticosterone secretion in rats during parturition was monitored, and the role of endogenous opioids in HPA axis regulation during birth was assessed. In particular, in control rats, the secretion of ACTH and corticosterone into the blood was suppressed during the entire parturition period, independent of the time of day of delivery (Fig. 4Go). Thus, delivery-related events (including labor, fetal expulsion, and performance of maternal behavior) were not accompanied by ACTH and corticosterone secretion. More remarkably, the plasma concentrations of both HPA axis hormones actually decreased in preparation for birth and declined further (compared with preparturition levels) after delivery of the second pup (Fig. 3Go).

The increase in plasma lactate concentration, at approximately 30–40 min after the onset of parturition, indicates a physical activation of the parturient rat, because plasma lactate is indicative of general motor activity and respiratory function. A close correlation between exposure to a physical stressor, for example forced swimming (35), and increase in plasma lactate and ACTH/corticosterone levels has been described. Thus, it can be concluded that the activity of the HPA axis is under efficient inhibitory control during parturition. Indeed, after application of the opiate antagonist NLX, the secretions of both ACTH and corticosterone were highly elevated during birth (Fig. 3Go), thus indicating a major role of endogenous opioids in the inhibition of HPA axis activity during parturition in rats (see below). The diurnal rhythm of the HPA axis (36) was present until the day before, but not on the day of, parturition, when ACTH and corticosterone levels remain at relatively high levels also between 0930 h and 1230 h (Fig. 2Go).

In rats showing prolonged phases of labor before or only rat "after", delivery of the first pup (Fig. 5CGo and 5DGo), HPA axis activity was increased. Although it remains to be investigated more thoroughly, this indicates that nonphysiological aberrations of the parturition process may provide additional stimuli, leading to an enhanced ACTH and corticosterone secretion. As such, it would be pertinent to test the responsiveness of the HPA axis to defined external, i.e. emotional or physical, stressors in the immediate peripartum period.

Inhibition of the HPA axis activity by endogenous opioids during birth
Recently we showed a stimulatory effect of endogenous opioids on HPA axis response to physical stress in virgin rats, an effect which is absent in late pregnancy (4). From the data obtained in this study, it may be concluded that this effect is further reversed at the time of parturition, resulting in a marked inhibition, by endogenous opioids, of ACTH and consequently corticosterone secretion.

However, there are contradictory reports regarding the effects of opiates and endogenous opioids on HPA axis secretory response in the virgin or male rat, dependent on the dose and route of administration (37), e.g. acute opiate treatment stimulated the release of ACTH and corticosterone in a dose-dependent manner (38, 39, 40, 41), and prior administration of NLX was shown to antagonize this effect (37), whereas Eisenberg et al. (42) reported a stimulatory effect of NLX on HPA axis hormone release.

The inhibitory effect of endogenous opioids on HPA axis activity during parturition, as reported in our study, could be expected to be primarily mediated via central, possibly hypothalamic, sites of action as µ-, {kappa}-, and {delta}-opioid receptors have been localized in the hypothalamus (43). Although a sparse opioid binding has been shown in the anterior pituitary (44), opioids were not found to affect the release of ACTH from the pituitary in vivo (45). Thus, the decrease in plasma ACTH levels, after the onset of parturition, might (at least in part) be mediated by hypothalamic opioids, possibly leading to a blunted release of ACTH secretagogues. However, because intrathecal administration of NLX blocks opioid-mediated analgesia during late pregnancy (46), the possibility that the increase in ACTH and corticosterone secretion after NLX administration, as described here, is caused by a reduction in pain threshold of the parturient rat has to be considered and is currently under investigation.

The finding that corticosterone secretion increased more rapidly than ACTH secretion after NLX administration (Fig. 3Go), may also suggest a direct inhibitory effect of endogenous opioids on adrenal corticosterone secretion during parturition. This hypothesis is further supported by reports showing that NLX increased plasma levels of corticosterone independent of ACTH secretion (41, 47). Studies in both virgin and male rats have described a direct potentiating effect of opioids on the adrenal steroidogenic response to ACTH (37), which seemed to be receptor-mediated and could be blocked by NLX (48).

Possible physiological implications of the reduced HPA axis activity during birth
Although still speculative, there are various possible explanations for the nonresponsiveness of the maternal HPA axis to parturition-related stimuli. First, this may be a useful mechanism to protect the mother rat from excessive metabolic changes during birth, because corticosterone will mobilize energy for physiological processes, with the result of reduced reserves available for further demands. Second, an enhanced activity of the HPA axis in the peripartum period may generally interfere with the normal process of parturition. A study by Mayer (49) showed that the application of ACTH to rats, from day 15 of pregnancy until parturition, resulted in a delayed birth or the death of the fetuses in utero, whereas stopping ACTH application on day 20 of pregnancy resulted in normal term labor and delivery of viable pups. Third, the possibility of a protective mechanism for the fetuses/neonates needs to be considered because, in most species, the maturation of the fetuses, including the maturation of neuronal structures, is still vulnerable to excessive levels of circulating corticosterone/cortisol in the peripartum period (50, 51). A progressive attenuation of the responsiveness of the HPA axis to external stimuli has been shown in the second half of rat pregnancy (5) and, thus, could be advantageous for the survival of the offspring. Another, though speculative, aspect is that an activated HPA axis may be associated with a behavioral activation that is analogous to an acute stress response and, thus, might be detrimental at the time of birth. Teleologically, an attenuated neuroendocrine response could contribute to mitigation of the risk of inadequate (e.g. escape) behavior during parturition.

Effects of NLX on the OXT system
In confirmation of earlier results (20, 21), it was shown that the plasma concentration of OXT increased significantly during parturition and was further enhanced after administration of NLX. However, in our study, NLX seemed to have no effect on the delivery process itself or on the performance of maternal behavior, which is in contrast to previous studies (20, 52). Inhibitory effects of endogenous opioids on the OXT system [in particular, at the end of pregnancy (19, 53) and during parturition (20, 32)] are well established phenomena; and both neurohypophysial {kappa}-receptors and hypothalamic µ-receptors are involved. In particular, it was recently demonstrated that endogenous opioids exert an inhibitory effect on the activity of OXT neurons within the hypothalamic supraoptic nucleus, possibly by suppressing the noradrenergic excitatory inputs to these neurons at the end of pregnancy (19). We could recently show that the release of OXT within the hypothalamic paraventricular nucleus, in response to a physical stressor, is inhibited by endogenous opioids at the end of pregnancy, but conversely, is stimulated in virgin rats (54). This reversal in the action of opioids on the OXT system demonstrates functional adaptations of hypothalamic neuroendocrine systems related to reproduction. Further studies are required to elucidate to what extent the effects of endogenous opioids on the activity of the HPA axis during parturition are mediated by centrally released OXT. An inhibitory influence of intracerebrally released vasopressin (55) and OXT (56) on basal ACTH secretion has been found, indicating differential involvement of these neuropeptides in HPA axis regulation.

In summary, during the rat’s parturition, the activity of the HPA axis (in comparison with preparturition conditions) is not enhanced (but rather, is suppressed) by parturition-related stimuli. Because ACTH and corticosterone secretions were greatly enhanced by NLX, the HPA axis is strongly inhibited by endogenous opioids in parturition. The physiological significance of this reproduction-related adaptation for protecting the pups’ and the mother’s well-being and survival needs to be further elucidated.


   Acknowledgments
 
The authors would like to thank Gabriele Kohl and Regina Herschel for the professional handling of the RIAs; and Drs. T. Day, R. Landgraf, and J. A. Russell for the critical reading of the manuscript.


   Footnotes
 
1 This work was supported by the Deutsche Forschungsgemeinschaft, from whom a Heisenberg-stipend (to I.D.N.) has been received. Back

Received October 27, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Lightman SL 1992 Alterations in hypothalamic-pituitary responsiveness during lactation. Ann NY Acad Sci 652:340–346[Medline]
  2. Walker CD, Trottier G, Rochford J, Lavallée D 1995 Dissociation of behavioral and hormonal responses to forced swim stress in lactating rats. J Neuroendocrinol 7:615–622[CrossRef][Medline]
  3. Waddell BJ, Atkinson HC 1994 Production rate, metabolic clearance rate and uterine extraction of corticosterone during rat pregnancy. J Endocrinol 143:183–190[Abstract]
  4. Douglas AJ, Johnstone HA, Wigger A, Landgraf R, Russell JA, Neumann ID 1998 The role of endogenous opioids in neurohypophysial and hypothalamo-pituitary-adrenal axis hormone secretory responses to stress in pregnant rats. J Endocrinol 158:285–293[Abstract]
  5. 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]
  6. Keller-Wood M 1995 Reflex regulation of hormonal responses during pregnancy. Clin Exp Pharmacol Physiol 22:143–151[Medline]
  7. Goland RS, Stark RI, Wardlaw SL 1990 Response to corticotropin-releasing hormone during pregnancy in the baboon. J Clin Endocrinol Metab 70:925–929[Abstract]
  8. Carr BR, Parker Jr CR, Madden JD, MacDonald PC, Porter JC 1981 Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 139:416–422[Medline]
  9. Nolten WE, Rückert PA 1981 Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 139:416–422
  10. Owens PC, Smith R, Brinsmead MW, Hall C, Rowley M, Hurt D, Lovelock M, Cang EC, Cubis J, Lewin T 1987 Postnatal disappearance of the pregnancy-associated reduced sensitivity of plasma cortisol to feedback inhibition. Life Sci 41:1745–1750[CrossRef][Medline]
  11. Douglas AJ, Russell JA 1994 Corticotropin-releasing hormone, proenkephalin A and oxytocin mRNAs in the paraventricular nucleus during pregnancy and parturition in the rat. Gene Ther [Suppl] 1:85
  12. Da Costa APC, Wood S, Ingram CD, Lightman SL 1996 Region-specific reduction in stress-induced c-fos mRNA expression during pregnancy and lactation. Brain Res 742:177–184[CrossRef][Medline]
  13. Toufexis DJ, Walker CD 1996 Noradrenergic facilitation of the adrenocorticotropin response to stress is absent during lactation in the rat. Brain Res 737:71–77[CrossRef][Medline]
  14. Summerlee AJ 1981 Extracellular recordings from oxytocin neurones during the expulsive phase of birth in unanaesthetized rats. J Physiol 321:1–9[Abstract/Free Full Text]
  15. Lightman SL, Young III WS 1989 Lactation inhibits stress-mediated secretion of corticosterone and oxytocin and hypothalamic accumulation of corticotropin-releasing factor and enkephalin messenger ribonucleic acids. Endocrinology 124:2358–2364[Abstract]
  16. Theodosis DT, Chapman DB, Montagnese C, Poulain DA, Morris JF 1986 Structural plasticity in the hypothalamic supraoptic nucleus at lactation affects oxytocin- but not vasopressin-secreting neurones. Neuroscience 17:661–678.[CrossRef][Medline]
  17. Neumann I, Russell JA, Landgraf R 1993 Oxytocin and vasopressin release within the supraoptic and paraventricular nuclei of pregnant, parturient and lactating rats: a microdialysis study. Neuroscience 53:65–75[CrossRef][Medline]
  18. Neumann I, Douglas AJ, Pittman QJ, Russell JA, Landgraf R 1996 Oxytocin released within the supraoptic nucleus of the rat brain by positive feedback action is involved in parturition-related events. J Neuroendocrinol 8:227–233[CrossRef][Medline]
  19. Douglas AJ, Neumann I, Meeren HKM, Leng G, Johnstone LE, Munro G, Russell JA 1995 Central endogenous opioid inhibition of supraoptic neurones in pregnant rats. J Neurosci 15:5049–5057[Abstract]
  20. Leng G, Mansfield S, Bicknell RJ, Brown D, Chapman C, Hollingsworth S, Ingram CD, Marsh MI, Yates JO 1987 Stress-induced disruption of parturition in the rat may be mediated by endogenous opioids. J Endocrinol 114:247–252[Abstract]
  21. Higuchi T, Tadokoro Y, Honda K, Negoro H 1986 Detailed analysis of blood oxytocin levels during suckling and parturition in the rat. J Endocrinol 110:251–256[Abstract]
  22. Boulfekhar L, Brudieux R 1980 Peripheral concentration of progesterone, cortisol, aldosterone, sodium and potassium in the plasma of the tadmit ewe during pregnancy and parturition. J Endocrinol 84:25–33[Medline]
  23. Brooks AN, Challis JRG 1987 Regulation of the hypothalamic-pituitary-adrenal axis in birth. Can J Physiol Pharmacol 66:1106–1112
  24. Lye SJ, Freitag CL 1990 Local and systemic control of myometrial contractile activity during labour in the sheep. J Reprod Fertil 90:483–492[Abstract]
  25. Gilbert CL, Lawrence AB, Forsling ML, Goode JA, McGrath TJ, McLean KA, Petherick JC 1996 Maternal plasma vasopressin, oxytocin and cortisol concentrations following foetal ejection in the pig. Anim Reprod Sci 43:137–150
  26. Lawrence AB, Petherick JC, McLean KA, Deans L, Chirnside J, Vaughan A, Clutton E, Terluow EMC 1994 The effect of environment on behaviour, plasma cortisol and prolactin in parturient sows. Appl Anim Behav Sci 39:313–330[CrossRef]
  27. Bacigalupo G, Langner K, Schmidt S, Saling E 1987 Plasma immunoreactive beta-endorphin, ACTH and cortisol concentrations in mothers and their neonates immediately after delivery - their relationship to the duration of labour. J Perinat Med 15:45–52[Medline]
  28. Fajardo MC, Florido J, Villaverde C, Oltras CM, González-Ramirez AR, González-Gómez F 1994 Plasma levels of ß-endorphin and ACTH during labor and immediate puerperium. Eur J Obstet Gyn Reprod Biol 55:105–108
  29. Gilbert CL, Boulton MJ, Forsling ML, Goode JA, McGrath TJ 1997 Restricting maternal space during parturition in the pig. Effects on oxytocin, vasopressin and cortisol secretion following vagino-cervical stimulation and administration of naloxone. Anim Reprod Sci 46:245–259[CrossRef][Medline]
  30. van Leengoed E, Kerker E, Swanson HH 1987 Inhibition of postpartum maternal behaviour in the rat by injecting an oxytocin antagonist into the cerebral ventricles. J Endocrinol 112:275–282[Abstract]
  31. Petraglia F, Baraldi M, Giarre G, Facchinetti F, Santi M, Volpe A, Genazzani AR 1985 Opioid peptides of the pituitary and hypothalamus: changes in pregnant and lactating rats. J Endocrinol 105:239–245[Abstract]
  32. Neumann I, Russell JA, Wolff B, Landgraf R 1991 Naloxone increases the release of oxytocin, but not vasopressin, within limbic brain areas of conscious parturient rats: a push-pull perfusion study. Neuroendocrinology 54:545–551[Medline]
  33. Landgraf R 1981 Simultaneous measurement of arginine vasopressin and oxytocin in plasma and neurohypophyses by radioimmunoassay. Endokrinologie 78:191–204[Medline]
  34. Landgraf R, Neumann I, Holsboer F, Pittman QJ 1995 Interleukin-1ß stimulates both central and peripheral release of vasopressin and oxytocin in the rat. Eur J Neurosci 7:592–598[CrossRef][Medline]
  35. Abel EL 1994 A further analysis of physiological changes in rats in the forced swim test. Physiol Behav 56:795–800[CrossRef][Medline]
  36. Atkinson HC, Waddell BJ 1995 The hypothalamo-pituitary-adrenal axis in rat pregnancy and lactation: circadian variation and interrelationship of plasma adrenocorticotropin and corticosterone. Endocrinology 136:512–520[Abstract]
  37. Pechnick RN 1993 Effects of opioids on the hypothalamo-pituitary-adrenal axis. Annu Rev Pharmacol Toxicol 32:353–382
  38. Kokka N, Garcia JF, Elliot HW 1973 Effects of acute and chronic administration of narcotic analgesics on growth hormone and corticotropin (ACTH) secretion in rats. Prog Brain Res 39:347–360[Medline]
  39. Zimmermann E, Critchlow V 1973 Inhibition of morphine-induced pituitary-adrenal activation by dexamethasone in the female rat. Proc Soc Exp Biol Med 143:1224–1226[Medline]
  40. Simon M, George R, Garcia J 1975 Acute morphine effects on regional brain amines, growth hormone and corticosterone. Eur J Pharmacol 34:21–26[CrossRef][Medline]
  41. Jezová D, Vigas M, Jurcovicová J 1982 ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone treated rats. Life Sci 31:307–314[CrossRef][Medline]
  42. Eisenberg RM 1980 Effects of naloxone on plasma corticosterone in the opiate naive rat. Life Sci 26:935–943[CrossRef][Medline]
  43. Desjardins GC, Brawer JR, Beaudet A 1990 Distribution of µ, {delta} and {kappa} opioid receptors in the hypothalamus of the rat. Brain Res 536:114–123[CrossRef][Medline]
  44. Simantow R, Snyder SH 1977 Opiate receptor binding in the pituitary gland. Brain Res 124:178–184[CrossRef][Medline]
  45. Pechnick RN, George R, Poland RE 1987 The effects of the systemic administration of N-methylmorphine chloride, a quaternary analogue of morphine that does not cross the blood-brain barrier, on the release of anterior pituitary hormones in the rat. Psychoneuroendocrinology 12:67–71[CrossRef][Medline]
  46. Sander HW, Gintzler AR 1987 Spinal cord mediation of the opioid analgesia of pregnancy. Brain Res 408:389–393[CrossRef][Medline]
  47. Hashimoto K, Suemaru S, Hattori T, Takao T, Inoue H, Sugawara M, Kageyama J, Ota Z 1986 Effects of (D-Ala2, Met5)-enkephalinamide and naloxone on ACTH and corticosterone secretion. Endocrinol Jpn 33:813–820[Medline]
  48. Heybach JP, Vernikos J 1981 Naloxone inhibits and morphine potentiates the adrenal steroidogenic response to ACTH. Eur J Pharmacol 75:1–6[CrossRef][Medline]
  49. Mayer G 1978 Action de l’ACTH synthétique (ß l-23 corticotrophine) sur la gestation et la parturition chez la ratte. Note de Guy Mayer presentée par MR Courrier. C R Acad Sci Paris, t. 286, Série D:879–882
  50. Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlanta P, Caldji C, Sharma S, Seckl JS, Plotsky PM 1996 Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 18:49–72[Medline]
  51. Weinstock M 1997 Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis? Neurosci Biobehav Rev 21:1–10[CrossRef][Medline]
  52. Rosenblatt JS, Mayer AD, Giordano AL 1988 Hormonal basis during pregnancy for the onset of maternal behavior in the rat. Psychoneuroendocrinology 13:29–46[CrossRef][Medline]
  53. Douglas AJ, Dye S, Leng G, Russell JA, Bicknell RJ 1993 Endogenous opioid regulation of oxytocin secretion through pregnancy in the rat. J Neuroendocrinol 5:307–314[Medline]
  54. Wigger A, Neumann ID 1998 Endogenous opioids suppress the stress-induced release of oxytocin (OXT) in the paraventricular nucleus (PVN) of the pregnant rat. J Neurosci [Suppl 10] 10:385 (Abstract No. 167.18)
  55. Wotjak CT, Kubota M, Liebsch G, Montkowski A, Holsboer F, Neumann I, Landgraf R 1996 Release of vasopressin within the rat paraventricular nucleus in response to emotional stress: a novel mechanism of regulating adrenocorticotropic hormone secretion? J Neurosci 16:7725–7732[Abstract/Free Full Text]
  56. Neumann ID, Torner L, Wigger A Oxytocin (OXT) released within the paraventricular nucleus (PVN) of pregnant rats: possible involvement in attenuated HPA axis activity. Program of the 19th Congress of The International Society of Psychoneuroendocrinology, Trier, Germany, 1998, p 116 (Abstract No. C132)



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