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

1985 ◽  
Vol 107 (3) ◽  
pp. 341-353 ◽  
Author(s):  
F. J. P. Ebling ◽  
G. A. Lincoln

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

1989 ◽  
Vol 122 (2) ◽  
pp. 509-517 ◽  
Author(s):  
R. J. E. Horton ◽  
H. Francis ◽  
I. J. Clarke

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


1995 ◽  
Vol 147 (3) ◽  
pp. 565-579 ◽  
Author(s):  
M L Barker-Gibb ◽  
C J Scott ◽  
J H Boublik ◽  
I J Clarke

Abstract Neuropeptide Y1–36 (NPY1–36) acts through Y1 and Y2 receptors while the C-terminal NPY fragments NPY18–36 and N-acetyl[Leu28,31]pNPY24–36 act only through the Y2 receptor. We have investigated the effects of intracerebroventricular (i.c.v.) administration of NPY1–36, NPY18–36 and N-acetyl[leu28,31]pNPY24–36 on LH secretion in the ovariectomised (OVX) ewe. These peptides were administered into a lateral ventricle (LV) or the third ventricle (3V) of OVX ewes during the non-breeding and breeding seasons. Microinjections of NPY were also made into the preoptic area (POA) during both seasons to investigate the effects of NPY at the level of the GnRH cell bodies. Tamed sheep were fitted with 19 gauge guide tubes into the LV, 3V or the septo-preoptic area (POA). Jugular venous blood samples were taken every 10 min for 3 h. Sheep were then given NPY1–36 (10 μg), NPY18–36 (100 μg) or saline vehicle into the LV; N-acetyl[Leu28,31]pNPY24–36 (100 μg), NPY1–36 (10 μg or 100 μg), NPY18–36 (10 μg or 100 μg) or saline vehicle into the 3V, or NPY1–36 (1 μg, 5 μg, 10 μg) into the POA. Blood sampling continued for a further 3 h. LH was measured in plasma by radioimmunoassay. LV or 3V injection of 10 μg NPY1–36 caused a small but significant (P<0·025) increase in the interval from the last pre-injection pulse of LH to the first post-injection LH pulse during the breeding season. Other LH pulse parameters were not significantly affected. NPY18–36 did not produce any significant change in LH pulsatility when injected into the LV, and neither peptide had any effect on plasma prolactin or GH levels. There was a significant (P<0·01) reduction in LH pulse frequency after 3V injection of 10 μg and 100 μg NPY and 100 μg NPY18–36. Pulse amplitude was reduced by 3V administration of the Y2 agonist, N-acetyl[Leu28–31]pNPY24–36 and 100 μ NPY18–36. When the amplitude of the first post-injection LH pulse was analysed, 10 μg NPY also had a significant (P<0·05) suppressive effect. During the non-breeding season, 100 μg NPY1–36 (but not 10 μg) decreased (P<0·01) LH pulse frequency. LH pulse amplitude was significantly (P<0·01) decreased by 100 μg NPY18–36. Doses of 10 μg NPY1–36 and 100 μg NPY18–36 had greater inhibitory effects on pulse frequency during the breeding season but the suppressive effect of 100 μg NPY was similar between seasons. Microinjections of NPY into the POA decreased (P<0·01) average plasma LH levels during the non-breeding season at a dose of 10 μg but did not significantly affect pulse frequency or amplitude. We conclude that a substantial component of the inhibitory action of NPY on LH secretion in the absence of steroids is mediated by the Y2 receptor. This inhibition is probably exerted by way of a presynaptic action on GnRH terminals in the median eminence as NPY does not modulate the frequency or amplitude of LH pulses at the level of the GnRH cell bodies in the POA. Journal of Endocrinology (1995) 147, 565–579


1997 ◽  
Vol 65 (2) ◽  
pp. 217-224 ◽  
Author(s):  
F. Forcada ◽  
J. M. Lozano ◽  
J. A. Abecia ◽  
L. Zarazaga

AbstractThe role of endogenous opioids and the dopaminergic system on the inhibition of luteinizing hormone (LH) secretion during early and late anoestrus, together with its modulation by the plane of nutrition were investigated in ewes with a short anoestrous season. In early anoestrus (22 March; day 0), two groups of ovariectomized, oestradiol-treated adult Rasa Aragonesa ewes, maintained under natural photoperiod at 41°N, were given enough food to provide 1·4 × (high; H; no. = 6) or 0·5 × (low; L; no. = 6) energy requirements for maintenance. The effects of administration of the opiate receptor antagonist naloxone (1 mg/kg at four 1-h intervals) (day 15) and of the dopaminergic2 receptor antagonist pimozide (0·08 mg/kg) (day 21) on LH secretion were assessed. A second experiment was carried out in late anoestrus (21 June) using the same protocol. A significant increase in LH pulse frequency after naloxone treatment for both H and L groups was detected in late anoestrus. Number ofLH pulses after naloxone injections in early anoestrus also increased in H (P < 0·05) and L ewes (P = 0·08). The effect of pimozide injection on mean LH pulse frequency was greater in early than in late anoestrus, especially in ewes receiving a high plane of nutrition (P < 0·05 and P = 0·07 for H and L ewes, respectively in April and P = 0·07 for H ewes in July). A significant increase of LH pulse amplitude was also detected in early anoestrus in H ewes (P < 0·01). These results provide evidence that endogenous opioid mechanisms are involved in the inhibition ofLH pulsatile release both in early and late anoestrus in ewes with a short seasonal anoestrus. The ability of pimozide to increase LH pulse frequency in early anoestrus could be enhanced by a high plane of nutrition in the breed studied.


1991 ◽  
Vol 71 (2) ◽  
pp. 333-342 ◽  
Author(s):  
W. D. Currie ◽  
S. J. Cook ◽  
N. C. Rawlings

Morphine (MOR) infusion (i.v.) was used to mimic effects of endogenous opioid peptides (EOPs) on LH secretion in ovariectomized (OVX) ewes during the breeding season and anestrum. MOR decreased luteinizing hormone (LH) pulse frequency and/or amplitude at higher doses (0.5 and 1.0 mg kg−1 h−1), and increased basal serum LH concentrations at a lower dose (0.01 mg kg−1 h−1). Simultaneous MOR and naloxone (NAL) infusion (0.5 mg kg−1 h−1, each) did not affect LH secretion, suggesting that effects of MOR were EOP receptor-specific. EOP involvement in ovarian steroid feedback was examined by NAL infusion and ovarian steroid replacement in OVX ewes. NAL infusion increased LH pulse frequency in OVX ewes during the breeding season, suggesting ovarian steroid-independent, but EOP-dependent suppression of LH secretion. NAL did not alleviate seasonal suppression of LH pulse frequency during the anestrum, suggesting ovarian steroid-independent, EOP-independent suppression of LH secretion. NAL eliminated progesterone (P4) suppression of LH pulse frequency during the breeding season, suggesting that a major portion of P4 feedback on tonic LH secretion is EOP-dependent. P4 replacement in the anestrum did not suppress LH pulse frequency. NAL infusion, following P4 replacement in the anestrum, increased LH pulse frequency to levels observed in untreated OVX ewes during the breeding season. It was concluded that EOP-dependent P4 feedback experimentally over-rode EOP-independent suppression of LH pulse frequency during the anestrum. EOP activity was not required for estradiol (E2) to suppress LH secretion from the pituitary during the breeding season. Key words: LH, morphine, naloxone, progesterone, estradiol


1986 ◽  
Vol 108 (1) ◽  
pp. 89-94 ◽  
Author(s):  
F. Petraglia ◽  
V. Locatelli ◽  
F. Facchinetti ◽  
M. Bergamaschi ◽  
A. R. Genazzani ◽  
...  

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


1983 ◽  
Vol 96 (2) ◽  
pp. 181-193 ◽  
Author(s):  
G. B. Martin ◽  
R. J. Scaramuzzi ◽  
J. D. Henstridge

The effects of oestradiol-17β, androstenedione, progesterone and time of the year on the pulsatile secretion of LH were tested in ovariectomized Merino ewes (n = 32). The steroids were administered by small subcutaneous implants, and the LH pulses were observed in samples taken at intervals of 15 min for 12 h in spring 1979, autumn 1980 and spring 1980, seasons corresponding to successive periods of anoestrus, breeding season and anoestrus. During spring, oestradiol alone was able to reduce the frequency of the LH pulses, while progesterone, either alone or in combination with oestradiol, had little effect. During autumn, on the other hand, neither oestradiol nor progesterone could significantly reduce the frequency of the pulses when administered independently, whereas the combined treatment was very effective. Androstenedione had no significant effect on pulse frequency at either time of the year, either alone or in any combination with oestradiol and progesterone. The basal levels of LH, over which the pulses are superimposed, were reduced by oestradiol alone in both seasons. Progesterone alone had no consistent effects, but interacted significantly with oestradiol and this combined treatment maintained low basal levels most effectively at all times. Androstenedione had no significant effect. The amplitude of the pulses increased throughout the course of the experiment. Within seasons, the amplitudes were significantly higher in the presence of oestradiol and progesterone, but were not significantly affected by androstenedione. It was concluded that certain of the ovarian steroids exert negative feedback on the tonic secretion of LH primarily by reducing the frequency of the pulses, and that the changes in LH secretion attributable to season and phases of the oestrous cycle can be accounted for entirely by the responses of the hypothalamus to oestradiol and progesterone. The role of the androstenedione secreted by the ovary in the ewe remains obscure.


1986 ◽  
Vol 111 (1) ◽  
pp. 67-73 ◽  
Author(s):  
M. J. D'Occhio ◽  
D. R. Gifford ◽  
T. Weatherly ◽  
B. P. Setchell

ABSTRACT To ascertain whether temporal changes in activity of the hypothalamo-pituitary axis in prepubertal bulls may occur independently of shifts in sensitivity to steroid feedback, the acute post-castration rise in serum gonadotrophins was monitored in bull calves castrated at monthly intervals from 4 to 9 months of age. Since a major feature of the gonadotrophin profiles of developing bulls is a change in LH pulse frequency early in life, pulsatile LH secretion after castration was used as an index of activity of the central LH-releasing hormone (LHRH) pulse generator. Relative to the day of castration (day 0) bull calves (n = 4) were bled at 20-min intervals for 8 h on day −3 and at 10-min intervals for 4 h on days 3, 5 and 7. During the first week after castration, 4-month-old bulls showed a higher (P<0·05) frequency of LH pulses compared with bulls at 8 and 9 months (1·13, 0·88 and 0·75 pulses/h respectively; pooled s.e.m.= 0·13). Mean LH levels before castration were higher (P<0·05) in 4-month-old bulls than in bulls at 7, 8 and 9 months (0·92, 0·37, 0·31, 0·38 μg/l respectively; pooled s.e.m. = 0·12). After castration mean LH levels did not differ with age. Mean FSH levels did not differ among age groups either before or after castration. Increased serum LH levels in 4-month-old bulls confirmed the transient rise in LH secretion that occurs at this time in developing bull calves. Age-related differences in LH pulse frequency observed after castration suggested that in prepubertal bulls changes in activity of the central LHRH pulse generator can occur independently of steroid feedback mechanisms. J. Endocr. (1986) 111, 67–73


2011 ◽  
Vol 211 (3) ◽  
pp. 263-272 ◽  
Author(s):  
Luis A Zarazaga ◽  
Irma Celi ◽  
José Luis Guzmán ◽  
Benoît Malpaux

This research examines which neural mechanisms among the endogenous opioid, dopaminergic, serotonergic and excitatory amino acid systems are involved in the stimulation of LH secretion by melatonin implantation and their modulation by nutritional level. Female goats were distributed to two experimental groups that received either 1.1 (group H;n=24) or 0.7 (group L;n=24) times their nutritional maintenance requirements. Half of each group was implanted with melatonin after a long-day period. Plasma LH concentrations were measured twice per week. The effects of i.v. injections of naloxone, pimozide, cyproheptadine andN-methyl-d,l-aspartate (NMDA) on LH secretion were assessed the day before melatonin implantation and again on days 30 and 45. The functioning of all but the dopaminergic systems was clearly modified by the level of nutrition, melatonin implantation and time elapsed since implantation. Thirty days after implantation, naloxone increased LH concentrations irrespective of the level of nutrition (P<0.05), similar to NMDA in the melatonin-implanted H goats (HM;P<0.01). On day 45, naloxone increased LH concentrations in the HM animals (P<0.05), similar to cyproheptadine in both the non-implanted H (HC) and the HM animals (P<0.01). Finally, at 45 days, NMDA increased the LH concentration in all subgroups (P<0.01). These results provide evidence that the effects of different neural systems on LH secretion are modified by nutritional level and melatonin implantation. Endogenous opioids seem to be most strongly involved in the inhibition of LH secretion on days 30 and 45 after melatonin implantation. However, the serotonergic mechanism appears to be most influenced by nutritional level.


Reproduction ◽  
2007 ◽  
Vol 134 (1) ◽  
pp. 137-145 ◽  
Author(s):  
Christina J McManus ◽  
Miroslav Valent ◽  
Steven L Hardy ◽  
Robert L Goodman

Seasonal anoestrus in the ewe results from enhanced oestrogen negative feedback. Recent data have implicated the ventromedial preoptic area (vmPOA) as an important site of oestrogen action. This study addressed whether NO acts within the vmPOA to inhibit LH during seasonal anoestrus. In Experiment 1, microimplants containingNω-nitro-l-arginine methyl ester (l-NAME, NOS inhibitor),S-methyl thiocitrulline (SMTC, neural NOS (nNOS) inhibitor) or empty implants (control) were administered during mid-anoestrus to the vmPOA.l-NAME, but not SMTC, significantly increased LH pulse frequency. For Experiment 2, ewes in late anoestrus were administered 7-nitroindazole (7NI; nNOS inhibitor),l-NAME, SMTC, or empty implants. 7NI, but notl-NAME or SMTC, increased LH pulse frequency. In Experiment 3, the effects of microimplants and microinjections ofl-NAME were compared in mid-anoestrus. Microinjections ofl-NAME (300 nl at 10 μg/μl) increased LH pulse frequency, but microimplants did not. In late anoestrus, similar microinjections were ineffective. Taken together, the results of Experiments 1–3 suggested that NO inhibition may be stronger during the middle than at the end of seasonal anoestrus. To test this hypothesis, ewes in Experiment 4 received microinjection ofl-NAME or vehicle thrice during the non-breeding season; none of the treatments increased LH pulse frequency. These results indicate that NO plays a role in the vmPOA in suppressing LH secretion during seasonal anoestrus because NOS inhibitors were consistently stimulatory when LH pulse frequency was low. However, the inconsistent and modest effects of these inhibitors suggest that NO actions in this area cannot completely account for the effects of inhibitory photoperiod.


Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 692-698 ◽  
Author(s):  
Kellie M. Breen ◽  
Fred J. Karsch

Abstract Elevations in glucocorticoids suppress pulsatile LH secretion in sheep, but the neuroendocrine sites and mechanisms of this disruption remain unclear. Here, we conducted two experiments in ovariectomized ewes to determine whether an acute increase in plasma cortisol inhibits pulsatile LH secretion by suppressing GnRH release into pituitary portal blood or by inhibiting pituitary responsiveness to GnRH. First, we sampled pituitary portal and peripheral blood after administration of cortisol to mimic the elevation stimulated by an immune/inflammatory stress. Within 1 h, cortisol inhibited LH pulse amplitude. LH pulse frequency, however, was unaffected. In contrast, cortisol did not suppress either parameter of GnRH secretion. Next, we assessed the effect of cortisol on pituitary responsiveness to exogenous GnRH pulses of fixed amplitude, duration, and frequency. Hourly pulses of GnRH were delivered to ewes in which endogenous GnRH secretion was blocked by estradiol. Cortisol, again, rapidly and robustly suppressed the amplitude of GnRH-induced LH pulses. We conclude that, in the ovariectomized ewe, cortisol suppresses pulsatile LH secretion by inhibiting pituitary responsiveness to GnRH rather than by suppressing hypothalamic GnRH release.


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