Corticotropin releasing hormone effects on peptidergic neurons of the hypothalamus.
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Animals↗
Biomedical subjects
O F Almeida
Publications and source records attributed to O F Almeida.
A model of chronic pain in the rat: functional correlates of alterations in the activity of opioid systems.
Intradermal inoculation of rats at the tail base with Mycobacterium butyricum led to the gradual development of an arthritic swelling of the limbs which peaked at 3 weeks and subsided thereafter. Arthritic rats displayed a loss of body weight, hypophagia, and hypodipsia in addition to a disruption of the diurnal rhythms of ingestive behavior and of core temperature. The activity of adenohypophyseal beta-endorphin-(beta-EP) secreting corticotrophs, in contrast to prolactin-(PRL) secreting lactotrophs, was increased in arthritic rats. Indeed, hypertrophy of the adrenal glands was seen. Arthritic rats also showed an elevation in spinal cord levels of immunoreactive dynorphin (DYN), an endogenous ligand of the kappa-opioid receptor. The paws and tail of arthritic rats showed lower thresholds in response to noxious pressure (hyperalgesia), higher thresholds in response to noxious heat (hypoalgesia), and no change in their response to noxious electrical stimulation. Neither naloxone nor ICI-154, 129 (a preferential delta-receptor antagonist) modified the responses of the paw or tail to pressure. However, MR 2266 (an antagonist with higher activity at kappa-receptors) decreased thresholds to pressure in arthritic, but not control, rats; that is, it potentiated the hyperalgesia. This action was stereospecific. None of the antagonists modified the response to heat. MR 2266 did not affect the response to pressure in rats with acute inflammation produced by yeast. Thus, the potentiation of pressure hyperalgesia by MR 2266 in chronic arthritic rats is highly selective. Arthritic rats showed a reduced response to the analgesic effect of a kappa-agonist (U-50,488H), whereas the response to a mu-agonist (morphine) was enhanced. These effects were specific to nociception in that their influence upon endocrine secretion (PRL and beta-EP) was otherwise changed. The secretion of beta-EP and PRL was stimulated by both morphine and U-50,488H, and the influence of U-50,488H upon the release of beta-EP (from the adenohypophysis) was enhanced in arthritic rats. It is suggested that polyarthritis is a complex condition entailing many changes, both behavioral and endocrinological. Further, arthritic rats cannot simply be described as "hyperalgesic": of critical importance is the nature of the nociceptive stimulus applied. The parallel alterations in spinal cord pools of DYN and kappa-receptors (see also Millan et al., 1986) and the changes in the influence on nociception of kappa-agonists and kappa-antagonists suggest an increased activity of spinal DYN. Thus, spinal kappa-receptors may play a role in the modulation of nociception under chronic pain.(ABSTRACT TRUNCATED AT 400 WORDS)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Stimulation of hypothalamic beta-endorphin and dynorphin release by corticotropin-releasing factor (in vitro).
Corticotropin-releasing factor (CRF) at doses of 10(-12)-10(-8) M significantly stimulated the release of beta-endorphin and dynorphin from superfused rat hypothalamic slices. These effects were shown to be mediated by the CRF receptor since they were antagonized by the CRF receptor antagonist alpha-helical CRF9-41 (10(-6) M). The two opioid peptides showed different time courses of response and in the case of beta-endorphin, an attenuation of the response upon continued exposure to CRF was observed.
Animals↗
Corticotropin-releasing factor (CRF) inhibits gonadotropin-releasing hormone (GnRH) release from superfused rat hypothalami in vitro.
A dose-dependent suppression of basal gonadotropin-releasing hormone (GnRH) release was observed when rat hypothalamic slices were superfused with human/rat corticotropin-releasing factor (CRF) (10(-12) to 10(-8) M). CRF was also found to significantly reduce the amount of GnRH released in response to 56 mM KCl. These in vitro results demonstrate that the CRF inhibition of GnRH secretion observed in vivo occurs within the hypothalamus and independently of the CRF activation of the pituitary-adrenal-gonadal axis.
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Stress-induced alterations in the levels of messenger RNA coding for proopiomelanocortin and prolactin in rat pituitary.
Acute stress promotes the secretion of prolactin (PRL) and of proopiomelanocortin (POMC)-derived peptides, adrenocorticotropic hormone and beta-endorphin, from the pituitary into the systemic circulation. The present study evaluates the influence of recurrent stress upon the biosynthetic activity of cells secreting these hormones in the rat. Chronic, intermittent, electrical foot-shock (3 mA,1 s duration, every 5 s for 30 min, twice daily) over a period of 1, 3 or 7 days caused an increase in messenger ribonucleic acid (mRNA) levels coding for POMC in the anterior pituitary. Maximally elevated mRNA levels were achieved after 3 days treatment (about 80% in excess of control values) which showed no further change at 7 days. These elevated levels of POMC mRNA were associated with increased levels of immunoreactive (ir)-beta-endorphin in the adenohypophysis following 7 days of stress treatment. In contrast, this treatment did not significantly alter mRNA levels coding for PRL in the anterior pituitary. Similarly, POMC mRNA levels in the intermediate/posterior pituitary were also not significantly altered during exposure to repeated stress. Similar changes in the biosynthesis of the pituitary hormones were seen in rats suffering from chronic arthritic pain for 3 weeks: there was an approximately 80% increase in POMC mRNA levels in the anterior pituitary which was associated with an increase in the levels of ir-beta-endorphin in this lobe and an increase in the plasma levels of ir-beta-endorphin. In contrast, there were no changes in the levels of mRNA coding for PRL in the adenohypophysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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In vivo and in vitro studies of GABAergic inhibition of prolactin biosynthesis.
The inhibitory action of gamma-aminobutyric acid (GABA) on prolactin (PRL) messenger ribonucleic acid (mRNA) levels was studied in vitro in rat anterior pituitary cells in culture and in intact rats in vivo. PRL mRNA levels were determined by hybridization of cytoplasmic RNA with a radiolabelled deoxyribonucleic acid probe complementary to rat PRL mRNA. Incubation of anterior pituitary cultures with GABA (10-100 microM) produced a dose-dependent decrease in PRL mRNA levels with half-maximal inhibition near 1 microM. The effect was time dependent and reversible after drug withdrawal. Inhibition by GABA was antagonized by bicuculline (10 microM) and mimicked by the GABAA receptor agonists muscimol and isoguvacine, but not with the GABAB agonist baclofen, indicating the involvement of GABAA receptors in the accumulation of PRL mRNA. To investigate the role of endogenous GABA on PRL biosynthesis in vivo, GABA levels were raised by using the GABA transaminase blockers vinyl GABA and ethanolamine-O-sulfate. Injection of vinyl GABA into rats (100 or 800 mg/kg every 2nd day) resulted in a dose- and time-dependent decrease in PRL mRNA levels in rat adenohypophysis. Similar results were obtained by addition of ethanolamine-O-sulfate to the drinking water (5 mg/ml, 250 mg/day). This treatment resulted in a rapid decrease of circulating PRL levels. This was followed by a delayed decrease in PRL mRNA concentrations in the adenohypophysis leading to a transient increase in hormone levels in the anterior pituitary. The results indicate that GABA has an inhibitory role on PRL secretion and PRL gene expression by a direct action at GABAA receptors on pituitary lactotrophs.
4-Aminobutyrate Transaminase↗
Opioid modulation of LHRH release in vitro depends upon levels of testosterone in vivo.
The in vitro release of LHRH from hypothalami of adult male rats (intact, 5-day castrates, 5-day castrates replaced with various doses of testosterone) was measured under basal conditions and after the addition of KCl, the opiate antagonist naloxone or the opiate agonist DAGO to the perifusion medium. Hypothalami from all treatment groups responded to 56 mM KCl with an increased output of LHRH. LHRH release was also induced by naloxone (10(-6)M), but only from tissues derived from intacts and castrates given physiological doses of testosterone. The opiate agonist DAGO (10(-6)M) did not alter the basal release of LHRH; it, however, caused a significant decrease in the K+-induced release of LHRH from hypothalami derived from intact rats and rats replaced with physiological levels of testosterone but not from those derived from castrate rats or castrate rats replaced with small amounts of testosterone. The specificity of this latter response was shown by its reversibility with naloxone. The lack of DAGO effects upon tissues from rats with low levels of steroid implied steroid dependency of the response to opioidergic influences and indeed, the response to DAGO was restored when testosterone was replaced at physiological doses. Measurement of hypothalamic LHRH content showed no significant differences between tissues obtained from intact, castrate and testosterone-replaced castrate rats. These in vitro data support the view that the inhibitory influence of opioids upon LHRH release depends on the presence of gonadal steroids in vivo.
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Paradoxical LH and prolactin responses to naloxone after chronic treatment with morphine.
A series of experiments was conducted in adult male rats to study the development of tolerance to and dependence on morphine in the neural processes controlling LH and prolactin secretion. The central mechanisms controlling both these hormones became tolerant following chronic application of the opiate agonist; this was seen in the form of diminished responsiveness to the agonist with time. There was an apparently greater degree of tolerance in the mechanisms regulating LH secretion than in those regulating prolactin secretion. In parallel experiments, the opiate antagonist naloxone was used to test for the development of dependence in rats chronically treated with morphine. While behavioural signs of physical dependence (withdrawal) were evident, the LH and prolactin responses proved to be the same as those observed in response to acute administration of opiate agonists (i.e. naloxone respectively decreased and increased serum LH and prolactin concentrations in animals chronically treated with morphine). This paper may represent the first report of such paradoxical responses to naloxone. It also demonstrates that opioid tolerance and dependence may exist as two separate phenomena in vivo.
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Regulation of hypothalamic beta-endorphin and dynorphin release by corticotropin-releasing factor (CRF).
Synthetic rat-human corticotropin releasing-factor (CRF), in doses between 10(-12) M and 10(-8) M, significantly stimulates the release of immunoreactive beta-endorphin and dynorphin-A from rat hypothalamic slices superfused in vitro. With prolonged exposure to CRF, there is a reduction in the release of both opioids which can be reversed by the addition of naloxone. The latter result indicates the involvement of autoregulatory mechanisms in the control of opioid neuronal function.
Animals↗
Inhibition of LH release by CRF may be partially mediated through hypothalamic beta-endorphin release.
Corticotropin releasing factor (CRF) given i.c.v. at doses of 0.02-2 nmol, significantly inhibited luteinising hormone (LH) secretion in castrate male rats. The luteinising hormone releasing hormone (LHRH) release from hypothalamic slices superfused in vitro with CRF (10(-12)M - 10(-8)M) was markedly reduced. In rats that had been infused with naloxone 2 days prior to testing with 0.2 nmol CRF, the effect of the CRF was significantly reduced. Together, these findings indicate that CRF inhibits LH secretion by inhibiting LHRH release from the hypothalamus, and that the latter action involves endogenous opioid peptides.
Animals↗
Melatonin: a coordinating signal for mammalian reproduction?
There is a daily rhythm in the production of the pineal hormone melatonin in all mammalian species. Production is stimulated by darkness and inhibited by light. This provides a signal reflecting the changing environmental lighting cycle. In seasonally breeding mammals that use changes in the photoperiod to time their reproductive cycles, temporal signals to the reproductive system are controlled by the daily rhythm in melatonin production.
Animals↗
Melatonin and malignant disease.
A possible role for the pineal and melatonin in malignant disease is suggested by the studies of hormone-dependent tumours presented here. The most dramatic observation of the effect of the pineal and melatonin in malignancy is that melatonin protects against, while pinealectomy enhances, 7,12-dimethylbenz[a]anthracene-induced mammary tumours in rats. Melatonin may protect against tumours through a suppressive effect on prolactin secretion or an action on oestrogen receptors. Melatonin can change the concentration of oestrogen receptors in hamsters, both juvenile and adults, and in a human breast cancer cell line. The long-term effect of melatonin in the ovariectomized adult hamster and in human breast cancer cells is to inhibit oestrogen-stimulated growth. A possible relationship between melatonin and oestrogen receptors was examined in women with breast cancer. An inverse correlation was observed between the oestrogen receptor concentration in each patient's tumour and her peak plasma melatonin level, suggesting that the more hormone dependent the breast cancer the more blunted the daily melatonin rhythm. Thus, the more robust the daily melatonin rhythm the greater the protective effect on hormone-dependent breast cancer. Unfortunately, this hypothesis is not easily tested as shown in a study of women at high risk for developing breast cancer. These women had daily melatonin profiles that did not differ from those of a normal population. Thus, the use of plasma melatonin as a screening tool for breast cancer risk is not reasonable; however the basic and clinical data argue that the role of melatonin in endocrine-related cancers requires more extensive clinical investigation.
9,10-Dimethyl-1,2-benzanthracene↗
Generation of melatonin rhythms.
In mammals, information about the environmental photoperiod is relayed from the retina to the suprachiasmatic nuclei (SCN) in the anterior hypothalamus and via the sympathetic nervous system to the pineal gland where it influences the secretion of melatonin. Light plays a dual role: to suppress the release of melatonin and to entrain the circadian rhythm generators in the SCN, which govern the endogenous melatonin rhythm. Under normal daily light-dark cycles melatonin secretion is confined to the dark period. In most photoperiodic species the daily pattern of secretion changes in response to changes in daylength, and this acts as a physiological time cue in the brain for the control of seasonal cycles in reproduction, moulting and other processes. To illustrate the underlying mechanisms that control the melatonin rhythm, results are presented from five experiments in which the blood plasma concentrations of melatonin were measured in Soay rams exposed to a variety of artificial changes in photoperiod including a switch from 16L:8D (16 h light:8 h dark) or 8L:16D to constant darkness, a switch from constant darkness to 1L:23D and a switch from 16L:8D to a 25 h or 23 h light-dark cycle. The results confirm that the melatonin rhythm is generated endogenously and will free-run under constant darkness with a period close to 24 h for at least 10 days. The rhythm can be entrained by exposure to IL:23D with the end of the light period acting as the 'melatonin-on' signal, and phase-shifts in the melatonin rhythm can be induced by phase-shifts in the light-dark cycle. The period for which melatonin concentrations are high each day (melatonin peak) also varies in duration under the different photoperiods, as a result of both the suppressive and the entraining effects of light. Two models explaining the control of melatonin peak duration are discussed.
Animals↗
Reproductive photorefractoriness in rams and accompanying changes in the patterns of melatonin and prolactin secretion.
Exposure of rams to alternating 16-week cycles of long and short days (16L:8D and 8L:16D) results in periods of testicular regression followed by testicular redevelopment, and there is an inverse relationship between the blood levels of prolactin and testis activity. In this study, two groups of rams were held under long or short day lengths for a period of 94 weeks. When held under either long or short days for more than 16 weeks, the animals showed spontaneous changes in gonadal activity and in the secretion of prolactin, both of which were no longer correlated with the prevailing photoperiod, i.e., they became photorefractory. The photorefractoriness was characterized by cyclical changes in testis function which were independent of day length. The period of these spontaneous cycles was similar during both treatment regimens (long days: 40.9 +/- 1.5 weeks; short days: 38.1 +/- 0.33 weeks), suggesting the presence of an endogenous pacemaker for the reproductive system. The changes in blood prolactin levels during photorefractoriness were no longer correlated with testis activity, and though cyclical, the period lengths differed under the two regimens (long days: 31.8 +/- 1.4 weeks; short days: 48.6 +/- 0.3 weeks). The rates of change in testis function and prolactin secretion were slower during the refractory state than during the photosensitive state. Upon switching the rams to a different photoperiod after the 94 weeks of exposure to fixed day lengths, the rams showed relatively rapid testicular and prolactin responses. Photoperiodic information appears to be relayed to the endocrine system through the daily pattern of melatonin secretion by the pineal. We measured the daily blood levels of melatonin on several occasions during phases of photosensitivity and photorefractoriness in the same group of rams. During the first 21 weeks under both lighting treatments, the rams showed synchronized daily patterns in their blood levels of melatonin, with elevated levels occurring mainly during the daily period of darkness. Similar synchronized daily rhythms were also seen when the rams were switched to a different photoperiod following 94 weeks of exposure to either long or short days. Between Weeks 21 and 94, the daily rhythms of melatonin did not occur consistently in all rams; often, the patterns differed markedly between individual rams held under the same day length and peak levels of melatonin were not always confined to periods of darkness.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Potency and specificity of a growth hormone-releasing factor in a primate and in vitro.
The potency and specificity of the 44-amino acid human pancreatic tumor GRF were tested in six adult female rhesus monkeys and in a perifusion system containing a suspension of rat pituicytes. In vivo, plasma GH levels were elevated in a dose-dependent fashion, with an ED50 of approximately 5 micrograms/kg, a value of the same order of magnitude as other hypothalamic releasing hormones. The magnitude of the GH response after GRF treatment was similar to that observed during insulin-induced hypoglycemia, with peak plasma GH concentrations occurring 5-15 min after GRF administration. High doses of GRF slightly stimulated PRL release, but had no effect on arterial blood pressure, heart rate, or plasma cortisol or glucose concentrations. In vitro, GRF released GH in a dose-dependent manner, but no PRL was released even at the highest GRF concentrations employed (100 nM). It thus appears that stimulation of PRL in vivo may be an indirect effect of GRF. Alternatively, there may be species differences in responsiveness to GRF.
Animals↗
Photoperiodic regulation of reproductive activity in the ram: evidence for the involvement of circadian rhythms in melatonin and prolactin secretion.
Adult Soay rams were housed under long days of 16L:8D for 16 weeks, and then exposed to a lighting regimen of either 8L:40D, 8L:28D, 8L:16D or maintained under 16L:8D. The diameter of the testes and the intensity of the sexual skin flush was recorded every 1-2 weeks, while on four occasions during the 8L:40D and 8L:28D regimens the concentrations of melatonin, prolactin and electrolytes (sodium and potassium) were measured in blood samples collected hourly for 2-4 days. During the initial period of 16L:8D, the testes of all rams regressed in size and the sexual skin flush disappeared. In the animals maintained under 16L:8D for more than 16 weeks, the testes began to redevelop spontaneously and there was a reappearance of the skin flush after 23-29 weeks. Compared to this group, the rams switched to 8L:40D and 8L:16D after 16 weeks showed a significant acceleration in testicular development and an earlier skin flush. The rams exposed to 8L:28D failed to show this stimulated response and reactivation of the testes was similar to that under prolonged 16L:8D. During the 16 weeks under 8L:40D there was a 3-fold increase in the 24-h mean plasma concentration of melatonin. A clearly defined 24-h rhythm in the levels of melatonin was evident during the treatment. The rhythm was synchronized in its timing for the different individuals in the group, while the peak levels of melatonin occurred earlier relative to the onset of the light period under 8L:40D compared to 16L:8D. Under the 8L:28D regimen there was an increase in the mean levels of melatonin as for 8L:40D; however, there was no consistent daily rhythm. Exposure to the two photoperiodic regimens also resulted in differences in the plasma profiles of prolactin, while no differences were evident for the levels of electrolytes. The combined results are used to develop a model for the photoperiodic control of the timing of the rhythm in secretion of melatonin is considered of central importance.
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Inhibition of reproduction in rams by long daylengths and the acute effect of superior cervical ganglionectomy.
Six castrated Soay rams were given testosterone implants, and exposed to an artificial lighting regimen of alternating 16-week periods of long days (16L:8D) and short days (8L:16D) for over 1 year. Under these conditions, the blood plasma concentration of testosterone was maintained relatively constant (4.3--6.4 ng/ml), while the levels of LH and prolactin varied in relation to the alterations in the photoperiod; low levels of LH occurred during long days when the rams were hyperprolactinaemic. During the last period of exposure to long days, 4 of the rams were cranially sympathectomized by removing the superior cervical ganglia. The effect of long daylengths on the secretion of LH and prolactin was blocked; prolactin concentrations began to decline after 2 weeks and LH levels increased. Ganglionectomy also influenced the plasma levels of melatonin; after the operation there was no longer a consistent 24-h rhythm in melatonin values and the increase associated with darkness was abolished. This results supports the view that the regulation of melatonin secretion is involved in the photoperiodic control of reproduction in rams.
Animals↗
Hourly fluctuations in the blood levels of melatonin, prolactin, luteinizing hormone, follicle-stimulating hormone, testosterone, tri-iodothyronine, thyroxine and cortisol in rams under artificial photoperiods, and the effects of cranial sympathectomy.
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