Oestrous cycle-related LH responsiveness to naloxone: effect of high oestrogen levels on the activity of opioid receptors

ABSTRACT Endogenous opioid peptides have a tonic inhibitory control on LH secretion, participating in the functional changes of the hypothalamic-pituitary-ovarian axis. To evaluate the activity of the endogenous opioid systems during the oestrous cycle, we measured plasma LH levels after naloxone administration (5 mg/kg, s.c.) at 09.00 and 16.00 h on all days of the cycle (two further measurements were taken at 14.00 and 18.00 h on the day of pro-oestrus) and after one dose or one week's treatment with oestradiol benzoate (OB; 0·2 μg/rat). Concentrations of LH were measured in the same experimental models after injection of LH-releasing hormone (LHRH; 1 μg/kg, i.p.) or saline. Naloxone induced a significant rise in LH levels on the day of oestrus, dioestrus day-1 and dioestrus day-2; this response was blunted on the morning of pro-oestrus and absent in the afternoon and after acute and chronic OB treatment. Conversely LHRH was most effective in increasing LH levels on the day of pro-oestrus and in OB-treated rats. These results indicate that opioid mechanisms, independently of the time of day and the pituitary responsiveness, exhibit a reduced activity when preovulatory changes occur, probably as a result of increased oestrogen levels. J. Endocr. (1986) 108, 89–94

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Fasting impairs LH secretion in female rats by activating an inhibitory opioid pathway

Journal of Endocrinology ◽

10.1677/joe.0.1050091 ◽

1985 ◽

Vol 105 (1) ◽

pp. 91-97 ◽

Cited By ~ 50

Author(s):

R. G. Dyer ◽

S. Mansfield ◽

H. Corbet ◽

A. D. P. Dean

Keyword(s):

Sampling Period ◽

Significant Rise ◽

Female Rats ◽

Opioid Antagonist ◽

Endogenous Opioid ◽

Opioid Mechanisms ◽

Before And After ◽

Naloxone Hydrochloride ◽

Lh Release ◽

Lh Secretion

ABSTRACT Two experiments were undertaken to investigate the way that fasting impairs LH secretion and to assess whether endogenous opioid mechanisms might be responsible for the impairment. In the first experiment, pulsatile LH secretion was measured in a total of 51 chronically ovariectomized female rats. Initially 29 rats were subjected to food withdrawal for 24, 48, 72 or 120 h before the experiment. When compared with data collected from eight unfasted control rats, the 120-h fast was found to reduce significantly the mean peak and trough values of the LH pulses measured. However, in a subsequent study, the inhibition of pulsatile LH secretion by a 120-h fast was prevented in a group of eight rats given the opioid antagonist naloxone hydrochloride before the start of the blood-sampling period. Naloxone was without effect on pulsatile LH secretion in eight unfasted control rats. In the second experiment, plasma LH concentrations were measured before and after unilateral electrical stimulation of the ventral noradrenergic tract (VNAT) in ovariectomized female rats pretreated with oestradiol benzoate. In 17 rats VNAT stimulation caused a significant rise in plasma LH, but after a 72-h fast this rise was significantly less than in unfasted control rats. However, pretreatment of fasted rats with naloxone (n = 9) significantly enhanced the VNAT-stimulated release of LH to the control values. Naloxone did not potentiate VNAT-stimulated LH release in unfasted animals (n = 6) or LH release in control unstimulated rats (n = 12). The experiments indicate that both pulsatile LH secretion, and LH release caused by VNAT stimulation, are impaired by an acute fast. In both cases, the impairment is prevented by pretreatment with naloxone. Thus fasting probably activates an inhibitory opioid pathway within the brain to inhibit LH secretion. J. Endocr. (1985) 105, 91–97

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Seasonal and steroid-dependent effects on the modulation of LH secretion in the ewe by intracerebroventricularly administered β-endorphin or naloxone

Journal of Endocrinology ◽

10.1677/joe.0.1220509 ◽

1989 ◽

Vol 122 (2) ◽

pp. 509-517 ◽

Cited By ~ 15

Author(s):

R. J. E. Horton ◽

H. Francis ◽

I. J. Clarke

Keyword(s):

Breeding Season ◽

Luteal Phase ◽

Pulse Frequency ◽

Opioid Peptide ◽

Follicular Phase ◽

Oestrous Cycle ◽

Opioid Antagonist ◽

Endogenous Opioid ◽

Endogenous Opioid Peptide ◽

Lh Secretion

ABSTRACT The natural opioid ligand, β-endorphin, and the opioid antagonist, naloxone, were administered intracerebroventricularly (i.c.v.) to evaluate effects on LH secretion in ovariectomized ewes and in ovariectomized ewes treated with oestradiol-17β plus progesterone either during the breeding season or the anoestrous season. Ovary-intact ewes were also studied during the follicular phase of the oestrous cycle. Jugular blood samples were taken at 10-min intervals for 8 h and either saline (20–50 μl), 100 μg naloxone or 10 μg β-endorphin were injected i.c.v. after 4 h. In addition, luteal phase ewes were injected i.c.v. with 25 μg β-endorphin(1–27), a purported endogenous opioid antagonist. In ovariectomized ewes, irrespective of season, saline and naloxone did not affect LH secretion, but β-endorphin decreased the plasma LH concentrations, by reducing LH pulse frequency. The effect of β-endorphin was blocked by administering naloxone 30 min beforehand. Treating ovariectomized ewes with oestradiol-17β plus progesterone during the breeding season reduced plasma LH concentrations from 6–8 μg/l to less than 1 μg/l. In these ewes, saline did not alter LH secretion, but naloxone increased LH pulse frequency and the plasma concentrations of LH within 15–20 min. During anoestrus, the combination of oestradiol-17β plus progesterone to ovariectomized ewes reduced the plasma LH concentrations from 3–5 μg/l to undetectable levels, and neither saline nor naloxone affected LH secretion. During the follicular phase of the oestrous cycle, naloxone enhanced LH pulse frequency, which resulted in increased plasma LH concentrations; saline had no effect. In these sheep, β-endorphin decreased LH pulse frequency and the mean concentrations of LH, and this effect was prevented by the previous administration of naloxone. The i.c.v. administration of β-endorphin(1–27) to luteal phase ewes did not affect LH secretion. These data demonstrate the ability of a naturally occurring opioid peptide to inhibit LH secretion in ewes during the breeding and non-breeding seasons, irrespective of the gonadal steroid background. In contrast, whilst the gonadal steroids suppress LH secretion in ovariectomized ewes during both seasons, they only appear to activate endogenous opioid peptide (EOP)-mediated inhibition of LH secretion during the breeding season. Furthermore, these data support the notion that LH secretion in ovariectomized ewes is not normally under the control of EOP, so that naloxone has no effect. Journal of Endocrinology (1989) 122, 509–517

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Endogenous opioids and the control of seasonal LH secretion in Soay rams

Journal of Endocrinology ◽

10.1677/joe.0.1070341 ◽

1985 ◽

Vol 107 (3) ◽

pp. 341-353 ◽

Cited By ~ 51

Author(s):

F. J. P. Ebling ◽

G. A. Lincoln

Keyword(s):

Breeding Season ◽

Chronic Treatment ◽

Seasonal Pattern ◽

Pulse Frequency ◽

Suppressive Effect ◽

Endogenous Opioids ◽

Endogenous Opioid ◽

Acute Increase ◽

Lh Releasing Hormone ◽

Lh Secretion

ABSTRACT Soay rams were treated with naloxone and/or morphine at different stages of their annual reproductive cycle to study the role of endogenous opioid peptides in the control of pulsatile LH secretion. The responses in intact rams were compared with those shown by pinealectomized (PNX) or superior cervical ganglionectomized (SCGX) rams which had a different annual testicular cycle. Naloxone (4–6 mg/kg i.v.) given to intact rams at four times of the year induced significant increases in LH pulse frequency in the breeding season in September and December, but minimal responses in the non-breeding season in June. Similar treatments given to PNX or SCGX rams induced good responses in March, June and September and the poorest response in December; the different seasonal pattern between the intact and PNX/SCGX rams was correlated with differences in the timing of their testicular cycles. Morphine (1 mg/kg i.v.) induced a significant decrease in LH pulse frequency when given to intact rams in October, but no significant effects were observed when morphine was given to sexually inactive rams in early July. Naloxone (1 mg/kg i.v.) given concurrently with morphine in October reversed the suppressive effect and resulted in an actual increase in LH pulse frequency above pretreatment levels. Morphine-treated rams showed normal LH responses to injections of LH-releasing hormone (LHRH) indicating that the site of opiate inhibition was on hypothalamic LHRH secretion rather than on pituitary LH release. Chronic treatment of intact and PNX rams with naloxone 1 mg/kg every 4 h for 7 days) in April and October produced the expected acute increase in LH pulse frequency in the intact rams in October, and at both times of year in the PNX rams, however there was no sustained increase in LH secretion in response to chronic naloxone in any of the treatment groups. The response to the second naloxone injection was much reduced and was absent after 3 days; responsiveness to naloxone was restored within 2 days of stopping the chronic treatment. The overall results indicate that an endogenous opioid mechanism is involved in the tonic inhibition of LH secretion and that this mechanism is most active in the breeding season when both naloxone and morphine have marked effects on pulsatile release of LH. Regulation of endogenous opioids in the hypothalamus may be part of the mechanism by which environmental factors modulate steroid negative-feedback control of LHRH and thus LH secretion in seasonally breeding mammals. J. Endocr. (1985) 107, 341–353

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A comparison of the effects of gonadal steroids on naloxone-induced LH secretion in gonadectomized rats

Journal of Endocrinology ◽

10.1677/joe.0.1100327 ◽

1986 ◽

Vol 110 (2) ◽

pp. 327-334 ◽

Cited By ~ 5

Author(s):

G. M. Spencer ◽

S. A. Whitehead

Keyword(s):

Inhibitory Effect ◽

Gonadal Steroids ◽

Ovariectomized Rats ◽

Endogenous Opioid ◽

Feedback Effects ◽

Serum Lh ◽

Gonadotrophin Secretion ◽

Endogenous Opioid Systems ◽

Hypothalamic Pituitary Axis ◽

Lh Secretion

ABSTRACT The effects of the opiate antagonist naloxone on serum LH concentrations was investigated in gonadectomized rats given different regimes of steroid pretreatment. Two injections of testosterone given 48 and 24 h before naloxone treatment failed to reinstate LH responses to this drug in castrated rats while subcutaneous testosterone-filled silicone elastomer capsules implanted for a week were effective in this respect. Injections of oestrogen, oestrogen plus progesterone or progesterone alone all restored LH responses to naloxone in ovariectomized rats when given 48 and/or 24 h before drug treatment, although the magnitude of these responses varied according to the precise steroid treatments. The hypothalamic-pituitary axis was also responsive to naloxone just before the progesterone-induced LH surge in oestrogen-primed ovariectomized rats. Results show that gonadal steroids are permissive to the effects of opiate drugs, but they suggest that endogenous opioid systems do not necessarily mediate the negative feedback effects of steroids. Some other factor(s), as yet unidentified in the rat, may control the opioid modulation of gonadotrophin secretion or exert an independent inhibitory effect on gonadotrophin release. J. Endocr. (1986) 110, 327–334

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Gonadal steroid modulation of naloxone-induced LH secretion in the rat

Journal of Endocrinology ◽

10.1677/joe.0.1010033 ◽

1984 ◽

Vol 101 (1) ◽

pp. 33-39 ◽

Cited By ~ 53

Author(s):

F. Petraglia ◽

V. Locatelli ◽

A. Pen̄alva ◽

D. Cocchi ◽

A. R. Genazzani ◽

...

Keyword(s):

Chronic Administration ◽

Significant Rise ◽

Endogenous Opioids ◽

Gonadal Steroids ◽

Female Rats ◽

Male Rats ◽

Opioid Antagonist ◽

Acute Administration ◽

Lh Releasing Hormone ◽

Lh Secretion

ABSTRACT The effect of acute administration of the opioid receptor antagonist naloxone hydrochloride (5 mg/kg, s.c.) on plasma LH levels was evaluated in female and male rats 24, 36 and 48 h and 1,3 and 5 weeks after gonadectomy and in 5-week gonadectomized rats after acute or chronic (2 weeks) administration of oestradiol benzoate (OB, 10 μg/rat per day, s.c.), testosterone propionate (TP, 150 μg/rat, s.c.) or dihydrotestosterone propionate (DHT, 150 μg/rat, s.c.) respectively. Concurrent evaluation of plasma LH after administration of LH releasing hormone (LHRH, 1 μg/kg, i.p.) was performed in the same experimental groups. In rats of both sexes, a significant rise in plasma LH after naloxone was observed in sham-operated and recently gonadectomized rats (24–48 h); in female rats 36 and 48 h after gonadectomy the rise was higher than in controls. One, 3 and 5 weeks after gonadectomy, naloxone failed to stimulate LH release in both female and male rats. In gonadectomized rats undergoing steroid replacement therapy, OB administered 72 h before testing, TP (16 and 72 h) and DHT (16 h) were the most effective in reinstituting the LH response to naloxone. Chronic administration of gonadal steroids did not restore normal LH responsiveness to naloxone. In most experimental groups, LH responses after naloxone were clearly unrelated to pituitary LH responsiveness to LHRH, which indicates that the opioid antagonist was acting via the central nervous system. In conclusion, these results demonstrate that: (1) gonadal steroids are critically important for the inhibitory effect of endogenous opioids on LH secretion to be manifested; (2) inhibition by the opiatergic system on LH secretion is more dependent on a modulatory action of gonadal steroids than on their simple presence or absence. J. Endocr. (1984) 101, 33–39

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Long-term consequences of prenatal exposure to morphine: Functional changes of the endogenous opioid systems

Toxicology Letters ◽

10.1016/0378-4274(94)90360-3 ◽

1994 ◽

Vol 74 ◽

pp. 56 ◽

Cited By ~ 1

Author(s):

R.J.M. Niesink ◽

J.M. van Ree

Keyword(s):

Prenatal Exposure ◽

Endogenous Opioid ◽

Functional Changes ◽

Endogenous Opioid Systems ◽

Long Term Consequences ◽

Opioid Systems

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Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01799 ◽

2005 ◽

Vol 34 (3) ◽

pp. 889-908 ◽

Cited By ~ 92

Author(s):

S Bauersachs ◽

S E Ulbrich ◽

K Gross ◽

S E M Schmidt ◽

H H D Meyer ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Cdna Array ◽

Transforming Growth Factor Β ◽

Early Embryo ◽

Oestrous Cycle ◽

Cdna Libraries ◽

Functional Changes ◽

Retinoic Acid Signalling ◽

Subtracted Cdna Libraries

The endometrium plays a central role among the reproductive tissues in the context of early embryo–maternal communication and pregnancy. It undergoes typical changes during the sexual/oestrous cycle, which are regulated by the ovarian hormones progesterone and oestrogen. To identify the underlying molecular mechanisms we have performed the first holistic screen of transcriptome changes in bovine intercaruncular endometrium at two stages of the cycle – end of day 0 (late oestrus, low progesterone) and day 12 (dioestrus, high progesterone). A combination of subtracted cDNA libraries and cDNA array hybridisation revealed 133 genes showing at least a 2-fold change of their mRNA abundance, 65 with higher levels at oestrus and 68 at dioestrus. Interestingly, genes were identified which showed differential expression between different uterine sections as well. The most prominent example was the UTMP (uterine milk protein) mRNA, which was markedly upregulated in the cranial part of the ipsilateral uterine horn at oestrus. A Gene Ontology classification of the genes with known function characterised the oestrus time by elevated expression of genes, for example related to cell adhesion, cell motility and extracellular matrix and the dioestrus time by higher expression of mRNAs encoding for a variety of enzymes and transport proteins, in particular ion channels. Searching in pathway databases and literature data-mining revealed physiological processes and signalling cascades, e.g. the transforming growth factor-β signalling pathway and retinoic acid signalling, which are potentially involved in the regulation of changes of the endometrium during the oestrous cycle.

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