Morphine does not stimulate prolactin release during lactation

The ability of morphine to stimulate prolactin and growth hormone (GH) release was investigated in male rats and in female rats during diestrus, proestrus and lactation. In agreement with previous reports, acute morphine administration produced an increase in circulating levels of prolactin in male and in diestrous and proestrous female rats. In contrast to these results, morphine administration (10 or 15 mg/kg, s.c.; 5 mg/kg, i.v.; 5 or 10 micrograms, i.c.v.) did not produce an increase in prolactin levels in lactating dams. Morphine stimulates prolactin release in part by decreasing dopamine turnover in the tuberoinfundibular neurons in the median eminence. In order to assess the functional activity of these neurons during lactation, haloperidol (0.1 or 0.5 mg/kg, i.v.) was given to lactating dams. There was a significant increase in prolactin levels following haloperidol administration, suggesting that these dopaminergic neurons are participating in the modulation of prolactin release during lactation. In contrast to the insensitivity of the lactating rat to morphine stimulation of prolactin release, the intraventricular administration of two other opiate receptor agonists, beta-endorphin (10 or 20 micrograms) and [D-Ala-D-Leu]enkephalin (DADLE; 5 or 10 micrograms), produced significant increases in circulating levels of this hormone. The GH response to morphine, beta-endorphin and DADLE was also measured in these same rats. All these opiate receptor agonists stimulated GH release in male rats and in female rats during diestrus and proestrus as well as during lactation. These observations suggest that the suckling stimulus during lactation renders the rat refractory to morphine stimulation of prolactin release, possibly as a result of down-regulation of the mu-opiate receptor subtype.     

Prolactin release and tuberoinfundibular dopaminergic neuronal activity following single and double injections of morphine

It is well established that opiate agonists alter tuberoinfundibular dopaminergic activity and consequently prolactin release. The purpose of this study was to characterize the effects of morphine on prolactin secretion and tuberoinfundibular dopaminergic neuronal activity with respect to time after administration. Additionally, the effect of an initial morphine injection on the response produced by a second injection of morphine was determined. The rate of depletion of median eminence dopamine content following synthesis inhibition byα-methyl-p-tyrosine was used as an index of dopaminergic neuronal activity. Male rats given a single injection of morphine sulfate (15 mg/kg, s.c.) showed a significant increase in circulating prolactin levels and had a lower rate of median eminence dopamine turnover 1 h after injection. Four hours after injection, circulating prolactin levels were similar to those in vehicle treated rats, while dopamine turnover was significantly higher than controls. When two injections of morphine sulfate (15 mg/kg, s.c.) were given 4 h apart, the stimulation of prolactin release produced by the second injection was significantly attenuated. Although this second injection caused a significant decrease in dopamine turnover, the turnover rate following this injection was significantly greater than that following the initial injection. The combination of fluoxetine and 5-hydroxytryptophan (FLX/5-HTP) caused an initial increase in prolactin secretion with plasma values returning to basal levels by 4 h. When rats were pretreated with FLX/5-HTP instead of morphine, the prolactin response to an injection of morphine 4 h later was not attenuated. Similarly a FLX/5-HTP pretreatment had no influence on a second injection of FLX/5-HTP administered 4 h later. The attenuation of a secretory response to a second morphine injection is specific to prolactin, since the growth hormone responses to the initial and the second injections of morphine were the same. These results indicate that the response of tuberoinfundibular dopaminergic neurons to morphine is biphasic. Following morphine administration, dopamine turnover is initially decreased but by 4 h turnover is increased above pretreatment rates. These alterations in dopamine turnover affect prolactin secretion such that release is initially stimulated, but 4 h later the response to a second morphine stimulation is attenuated.     

Central Nervous System Sites of Action of an Enkephalin Analogue, (D-Met2, Pro5)-Enkephalinamide, and Naloxone on the Secretion of Five Anterior Pituitary Hormones of Male Rats

Central nervous system sites of action of opioid peptides on pituitary hormone secretion were investigated. One nmol of an enkephalin analogue, (D-Met², Pro⁵)-enkephalinamide, and 10 nmol of the opiate antagonist naloxone were injected into ten different regions of the brain of conscious male rats and their effect on the release of five anterior pituitary hormones tested. The injections were made through a special injection cannula which was inserted into the brain through a guide cannula fixed on the skull and implanted into the brain 5 to 7 days earlier. Both compounds injected into the medial septum, medial preoptic area and hypothalamic paraventricular nucleus affected prolactin, growth hormone and luteinizing hormone (LH) secretion. The enkephalin analogue stimulated prolactin and growth hormone and inhibited LH release. Naloxone induced the opposite effect. Drugs given into the hypothalamic ventromedial nucleus caused changes in plasma prolactin and growth hormone levels. Enkephalinamide increased and naloxone decreased plasma concentrations of both hormones. Administration of the compounds into the dorsal raphe area resulted in alterations of prolactin and LH release, the analogue caused elevation of prolactin and inhibition of LH release, whereas the opiate antagonist resulted in opposite changes. Only an LH response was obtained from the hypothalamic dorsomedial nucleus and a growth hormone response from the central amygdala. Also in these cases the enkephalin analogue decreased LH and elevated growth hormone plasma levels, and naloxone brought about a rise in LH and a diminution of growth hormone concentration. None of the regions were effective in inducing a clear-cut adrenocorticotrophin or follicle-stimulating hormone response. The parietal cortex, medial amygdala and the dentate gyrus were entirely ineffective sites. The findings suggest that in the brain there are multiple sites of action of opioids on pituitary trophic hormone secretion and the effective sites are not identical in terms of pituitary hormone response.     

In vivo and in vitro effects of cholecystokinin on gonadotropin, prolactin, growth hormone and thyrotropin release in the rat

Varying doses of cholecystokinin (CCK) dissolved in 2 μl of 0.9% NaCl or 2 μl of saline alone were injected into the third ventricle of conscious ovariactomized (OVX) rats bearing 3rd ventricular cannulae. Plasma luteinizing hormone (LH), prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and follicle stimulating hormone (FSH) levels were measured by RIA in jugular blood samples drawn through an indwelling silastic cannula. Control injections of saline i.v. or into the 3rd ventricle did not modify plasma hormone levels. Intraventricular injections of 4, 40 and 500 ng CCK produced a significant suppression of plasma LH within 5 min of injection. Injection of 4 or 500 ng doses of CCK has no effect on plasma PRL levels, but injection of the 40 ng dose produced a significant elevation of plasma PRL within 15 min. Plasma GH levels increased significantly within 15 min of the 3rd ventricular injection of each dose of CCK. The 40 ng dose of CCK caused a progressive reduction of plasma TSH which was significant by 15 min and lasted through the 60 min of experimentation. The highest dose of 500 ng reduced plasma TSH levels within 5 min. Plasma FSH was not altered by any dose of CCK. Intravenous injection of CCK caused a dose-related increase in plasma prolactin levels within 5 min, but only the highest dose of 1000 ng produced a significant decrease in plasma LH. No significant changes in GH, TSH or FSH levels were observed after i.v. injection of CCK. In vitro incubation of hemipituitaries from male rats with doses of CCK ranging from 10 ng to 5 μg had no effect on pituitary hormone release into the medium. The results indicate that CCK can alter pituitary hormone release via a hypothalamic action and suggest that it may act as t transmitter or modulator of neuronal activity controlling the release of hypothalamic releasing and/or inhibiting hormones.     

Intraventricular morphine produces pain relief,hypothermia, hyperglycaemia and increased prolactin and growth hormone levels in patients with cancer pain

Summary The effects of analgesic, thermoregulatory and endocrine functions of administering morphine sulphate (0.3mg) into the lateral cerebral ventricle via an Ommaya catheter were assessed in eight patients with cancer pain. Satisfactory control of intractable pain was obtained in these patients, without any change in other sensory modalities. The delay in the onset of pain relief and the duration of analgesia ranged, respectively, from 20 to 40 min and from 12 to 16 h after drug injection. In addition, intraventricular administration of morphine caused a reduction in rectal temperature in these patients at an ambient temperature of 24°C. The hypothermia in response to the injection of morphine was due to cutaneous vasodilation and sweating. There was no change in metabolism or in respiratory evaporative heat loss after morphine injection. Further, 10 to 20 min after intraventricular administration of morphine, the blood levels of prolactin, growth hormone and glucose were elevated in these patients. The changes in temperature and endocrine levels lasted for 1–3 h. In addition to the pain relief, these side-effects of morphine treatment were short-lasting and disappeared as the morphine treatment continued. The results indicate that activation of opiate receptors in the brain produced pain relief, hypothermia (due to cutaneous vasodilation and sweating), and increased blood levels of prolactin, growth hormone and glucose in patients with cancer pain.     

Mu-Selective Opioid Peptides Stimulate Prolactin Release in Lactating Rats

The fact that opiates elicit prolactin secretion is well known. However, we have recently discovered that morphine does not stimulate prolactin release in lactating rats. The physiological basis for this alteration in opiate sensitivity during lactation is not known. Since morphine-induced prolactin secretion in male rats is mediated via the mu opioid receptor subtype, one possible explanation is that mu receptors are down-regulated during lactation. To address this possibility, the effects of mu opioid peptides on prolactin secretion were examined in lactating rats. The presumed mu-selective peptides DAGO ([D-Ala², Me-Phe⁴, Gly-ol⁵]-enkephalin) and PLO-17 ([NMe-Phe³, D-Pro⁴]-morphiceptin) were administered to primiparous lactating rats and the resulting hormone responses measured. Both DAGO and PLO-17 caused a rapid and significant rise in plasma prolactin during lactation. The prolactin-releasing effects of both peptides were naloxone reversible, suggesting involvement of opioid receptors. Moreover, the DAGO-induced secretion of prolactin could be completely abolished by pretreatment with the irreversible mu antagonist β-funaltrexamine. In lactating rats, DAGO and PLO-17 were poor growth hormone-releasing agents, providing further evidence for the mu specificity of these peptides. These results imply that during lactation, as in other reproductive states, mu opioid receptor sites are positively coupled to the prolactin secretory mechanism. Thus, the previously observed inability of morphine to elicit prolactin release in lactating rats cannot be explained on the basis of down-regulation of mu opioid receptors.     

Hypothalamic opioid receptors mediate the inhibitory actions of corticotropin-releasing hormone on luteinizing hormone release: further evidence from a morphine-tolerant animal model

Recent experiments have shown that corticotropin-releasing hormone (CRH) inhibits gonadotropin hormone-releasing hormone (GnRH) and luteinizing hormone (LH) release, and endogenous opioid peptides have been implicated in the mediation of these effects. To further test this hypothesis, the effects of CRH on LH secretion was tested in rats that were made tolerant to the alkaloid opiate agonist morphine. Male rats were gonadectomized and 5 days later implanted with 2 pellets containing 75 mg of morphine each, for 48 h and with a third morphine pellet for the following 24 h. Rats were killed on the 4th day and their serum levels of LH were found to be similar to those of placebo-treated controls, indicating that the neural systems controlling LH secretion had become tolerant to the chronic exposure to morphine. The tolerant condition was confirmed in a subgroup of morphine-treated rats since an acute injection of morphine (5 or 10 mg/kg) did not further suppress LH levels in the chronically morphinized rats. The LH-suppressive efficacy of CRH (0.2 nmol, i.c.v.) was found to be markedly reduced in these morphine-tolerant rats compared to the opiate-naive animals. This finding thus further supports the view that opioid receptors partially mediate the inhibitory actions of CRH upon the GnRH-LH system.     

Acute and chronic morphine effects on plasma corticosteroids and growth hormone in the cat

(1) Low doses of intravenous morphine in the cat caused an elevation of both corticosteroid and growth hormone in plasma. (2) Corticosteroid levels did not continue to increase in concert with the dose of morphine but the level of growth hormone did. (3) Tolerance developed to the effects of morphine on corticosteroids but not to the effect on growth hormone. (4) Naloxone precipitated withdrawal was associated with an increase in plasma corticosteroid but not growth hormone.     

Central neuropeptide B administration activates stress hormone secretion and stimulates feeding in male rats

Neuropeptide B (NPB) was identified to be an endogenous, peptide ligand for the orphan receptors GPR7 and GPR8. Because GPR7 is expressed in rat brain and, in particular, in the hypothalamus, we hypothesized that NPB might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPB were observed on the in vitro releases of prolactin, adrenocorticotropic hormone (ACTH) or growth hormone (GH) when log molar concentrations ranging from 1 pM to 100 nM NPB were incubated with dispersed anterior pituitary cells harvested from male rats. In addition NPB (100 nM) did not alter the concentration response stimulation of prolactin secretion by thyrotropin-releasing hormone, ACTH secretion by corticotropin-releasing factor (CRF) and GH secretion by GH-releasing hormone. However, NPB, when injected into the lateral cerebroventricle (i.c.v.) of conscious, unrestrained male rats, elevated prolactin and corticosterone, and lowered GH levels in circulation. The threshold dose for the effect on corticosterone and prolactin levels was 1.0 nmol, while that for the effect on GH release was 3.0 nmol NPB. Pretreatment with a polyclonal anti-CRF antiserum completely blocked the ability of NPB to stimulate ACTH release and significantly inhibited the effect of NPB on plasma corticosterone levels. NPB administration i.c.v. did not significantly alter plasma vasopressin and oxytocin levels in conscious rats. It did stimulate feeding (minimum effective dose 1.0 nmol) in sated animals in a manner similar to that of the other endogenous ligand for GPR7, neuropeptide W. We conclude that NPB can act in the brain to modulate neuroendocrine signals accessing the anterior pituitary gland, but does not itself act as a releasing or inhibiting factor in the gland, at least with regard to prolactin, ACTH and GH secretion.     

Effect of clonidine on the secretion of anterior pituitary hormones in heroin addicts and normal volunteers

Neuroendocrine effects of intravenous injections of clonidine, 0.15 mg, were investigated in 13 heroin addicts and 14 normal control subjects. The study was designed to determine whether continuous opiate administration leads to the development of hypersensitive alpha 2-adrenergic receptors. The peak increments in levels of plasma growth hormone (GH) and beta-endorphin induced by clonidine did not differ between heroin addicts and normal control subjects. At no time interval could the clonidine-induced rise in GH levels in addicts be differentiated from that induced by placebo. Clonidine failed to alter plasma prolactin, gonadotropin, or thyrotropin levels in either heroin addicts or controls. Since clonidine's neuroendocrine effects are reportedly due to the activation of postsynaptic alpha 2-adrenoceptors, it appears that (1) continuous opiate use does not lead to the development of hypersensitive alpha 2-adrenergic receptors involved in neuroendocrine mechanisms and (2) brain norepinephrine does not play a role in the regulation of tonic prolactin, gonadotropin, and thyrotropin secretion in man.     

Multiple hormonal responses to morphine: relationship to diagnosis and dexamethasone suppression

Plasma cortisol, prolactin (PRL), growth hormone (GH), and thyroid stimulating hormone (TSH) responses to intravenous morphine (0.1 mg/kg body weight) were investigated in five healthy women and 22 female psychiatric inpatients (eight with major depression, 12 with schizophrenia and two with personality disorders) during a 120 min period. The results were also related to a subsequent dexamethasone suppression test (DST). Morphine caused a strong and progressive decline in plasma cortisol which was uniform in controls, depressed, and nondepressed patients. DST nonsuppressors had significantly higher cortisol levels during the entire period, but the same response to morphine. Morphine strongly stimulated PRL secretion, which was found to be significantly smaller in patients than in controls, but no difference was seen between depressed and nondepressed subjects. GH and TSH showed only minor and variable changes after morphine, with no overall significant differences. The data in this study do not support the assumption of a major alteration in opiate receptor responsivity either in depression or in DST nonsuppressor patients insofar as the regulation of the adrenal, thyroid, GH and PRL hormone secretion is concerned.     

Failure of naloxone to reverse apomorphine effects in humans

Twelve male volunteers given apomorphine (20 micrograms/kg/hr) for 40 min by i.v. infusion had significant changes in growth hormone, prolactin, vasopressin, pulse rate, sedation and nausea. Naloxone, (20 mg i.v.) or placebo given in a double-blind manner 10 min before the end of the apomorphine infusion as a concealed bolus did not alter the effects of apomorphine. Vasopressin rise correlated significantly with nausea intensity. We conclude that acute opiate receptor blockade does not reverse most apomorphine effects.     

Pulsatile cerebrospinal fluid and plasma ghrelin in relation to growth hormone secretion and food intake in the sheep

As in other species, exogenous administration of ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptors can stimulates feeding behaviour and GH secretion in the sheep. However, the importance of endogenous ghrelin for these two functions as well as its central or peripheral origin remained to be established. In the present study, cerebrospinal fluid (CSF) ghrelin concentrations were measured in five anoestrous ewes and found to be more than 1000-fold lower than circulating plasma levels, in keeping with the even lower concentration in hypothalamic compared to abomasum tissue extracts. Cluster analysis indicated that CSF ghrelin levels were markedly pulsatile, with a greater number of peaks than plasma ghrelin. Pulsatility parameters were closer for GH and CSF ghrelin than between GH and plasma ghrelin. Plasma ghrelin and GH levels were significantly correlated in three out of five ewes but CSF ghrelin and GH in one ewe only. Half of the CSF ghrelin episodes were preceded by a ghrelin peak in plasma with a 22-min delay. Cross-correlations between plasma GH and plasma or CSF ghrelin did not reach significance but a trend towards cross-correlation was observed from 20 to 0 min between plasma and CSF ghrelin. At 09.00 h, when food was returned to ewes, voluntary food intake did not elicit a consistent change in plasma or CSF ghrelin levels. By contrast, a peripheral ghrelin injection (1 mg, i.v.) immediately stimulated feeding behaviour and GH secretion. These effects were concomitant with a more than ten-fold increase in plasma ghrelin levels, whereas CSF ghrelin values only doubled 40-50 min after the injection. This suggests that peripherally-injected ghrelin crosses the blood-brain barrier, but only in low amount and with relatively slow kinetics compared to its effects on GH release and food intake. Taken together, the results obtained in the present study support the notion that, in the ovariectomised-oestradiol implanted sheep model, peripheral ghrelin injection rapidly induces GH secretion, and feeding behaviour, probably by acting on growth hormone secretagogue receptor subtype 1 located in brain regions in which the blood-brain barrier is not complete (e.g. the arcuate nucleus).     

The effects of intraventricular prolactin infusions on pituitary responsiveness to thyrotropin-releasing hormone, 5-hydroxytryptophan or morphine in rhesus monkeys

The effects of intraventricular infusions of ovine prolactin (oPrl) on both endogenous prolactin levels in serum, and upon the release of prolactin and cortisol in response to treatment with either TRH, 5-HTP or morphine were studied in rhesus monkeys. A single injection of oPrl (10.8 μg) into the lateral ventricles of castrated males resulted in CSF levels of around 350 ng/ml 60 min later, but no oPrl could be detected in the blood. Endogenous (rhesus) prolactin levels in serum fell during this time to about half their initial values in oPrl-treated animals but not in the bovine serum albumin (BSA)-injected controls. Ovine prolactin was infused continuously into either the lateral or third ventricles of ovariectomized, estrogen-treated females for 6 days from an osmotic minipump (2.7 μg/h). CSF levels of oPrl were about 250 ng/ml though none was found in the serum. The release of endogenous prolactin by TRH (1 μg) was greatly reduced compared with BSA-treated controls. 5-HTP (2.5 mg/kg together with carbidopa pretreatment) also stimulated much less prolactin release in females chronically infused with oPrl and there was some evidence for a similar effect in males following a single intraventricular injection. CSF levels of 5-HTP itself, and of 5-HIAA and HVA were similar throughout this experiment in both oPrl and BSA-infused animals. Finally, prolactin released by morphine (5 mg) was highly attenuated in females receiving oPrl intraventricularly.In contrast to those on serum prolactin, the effects of these various treatments on serum cortisol were unaltered by intraventricular oPrl.These results suggest that the primate brain contains a neural system which is directly responsive to prolactin, and which can modulate this hormone's release under either basal conditions or following treatment with substances that stimulate its release by acting either directly on the pituitary or upon the neural systems regulating pituitary function. These results are compatible with the presence of increased dopamine in the portal blood, though this was not measured in these experiments.     

Release of Oxytocin into Blood and into Cerebrospinal Fluid Induced by Naloxone in Anaesthetized Morphine-Dependent Rats: The Role of the Paraventricular Nucleus

Opioid actions on oxytocin secretion into blood and cerebrospinal fluid (CSF) were investigated in urethane-anaesthetized female rats after intracerebroventricular (icv) infusion of morphine sulphate or vehicle for 5 days. Serial femoral arterial blood samples and cisterna magna CSF samples were collected for radioimmunoassay. Naloxone was given to assess endogenous opioid tone in icv vehicle-infused rats and to precipitate withdrawal in morphine-dependent animals. Initial plasma oxytocin concentration was not affected by icv morphine infusion. In control rats receiving icv vehicle, naloxone increased plasma oxytocin 11-fold within 5 min, and in icv morphine-infused rats, naloxone increased plasma oxytocin 80-fold within 5 min. In both groups, 90 min after naloxone plasma oxytocin was still 5 and 10 times, respectively, the initial concentration. Without naloxone, neither plasma nor CSF oxytocin concentration changed significantly with time (up to 90 min) in either icv treatment group. In the icv vehicle group, there was a 2-fold increase in CSF oxytocin 90 min after naloxone. In the icv morphine-infused group, CSF oxytocin was increased 5-fold 40 min after naloxone. In another group of icv morphine-infused rats, intravenous infusion of oxytocin to achieve plasma levels similar to those seen after naloxone, did not significantly increase CSF oxytocin. In a further group of icv morphine-infused rats, [³H]oxytocin was infused intravenously immediately after naloxone was given; in these rats oxytocin transfer from blood to CSF could account at most for only 20% of the increase in CSF oxytocin after naloxone. A further group of rats underwent bilateral microknife ablation of the paraventricular nuclei (PVN) 9 days before icv vehicle or morphine infusions were started; blood and CSF samples were collected under urethane anaesthesia. Initial concentrations of oxytocin in CSF and in plasma were similar in both groups with PVN ablation. In all PVN-lesioned rats initial plasma concentrations of oxytocin were undetectable (<5 pg/ml) and thus less than in intact rats. In contrast, initial levels of oxytocin in CSF were 8-fold greater in PVN-lesioned rats than in intact animals. Naloxone increased plasma oxytocin concentration in the icv vehicle group at least 10-fold within 30 min and in the icv morphine group at least 100-fold within 5 min. CSF oxytocin in the icv vehicle group was not altered by naloxone, but in the icv morphine group CSF oxytocin was increased 5-fold 40 min after naloxone. There were no consistent differences between the icv vehicle- and icv morphine-treated groups in the initial plasma levels of vasopressin, growth hormone and adrenocorticotrophin; PVN ablation did not affect adrenocorticotrophin levels. After naloxone growth hormone levels did not change, vasopressin concentration rose moderately only after 90 min and only in the icv vehicle-treated group, and adrenocorticotrophin concentrations decreased with time whether or not naloxone was given. The results imply an endogenous opioid tone on neurons releasing oxytocin into CSF, and morphine-dependence of these neurons. Furthermore, in PVN-lesioned rats, magnocellular supraoptic neurons could be a source of oxytocin release into CSF.     

Morphine but not Naloxone Enhances Luteinizing Hormone-Releasing Hormone Neuronal Responsiveness to Norepinephrine

Some axon terminals of hypothalamic opiate neurons directly synapse on luteinizing hormone-releasing hormone (LHRH) neurons. To determine whether such synaptic connections affect LHRH neuronal activity, we have examined the profiles and concentrations of LH released in response to intracerebroventricular (icv) norepinephrine (NE, 45 μg) infusions alone or following medial preoptic area (MPOA) electrochemical stimulation (ECS) in estrogen-treated ovariectomized rats. Similar studies were performed in rats treated with naloxone (5 mg/kg ip) or morphine (20 mg/kg sc) given 15 min prior to MPOA-ECS or 30 min prior to icv NE. Naloxone neither augmented nor suppressed the LH response obtained with NE alone. MPOA-ECS evoked a significant increase in plasma LH. When the preoptic area was stimulated (0 min) and NE was infused at 30 min, a significant amplification of LH release occurred. Prior treatment of rats (-15 min) with naloxone had no effect on LH responses elicited by either preoptic stimulation alone or combined with icv NE. In the second study, morphine was given sc and had no effect on basal plasma LH levels. However, when morphine was given (-15 min) and icv NE infusions were made (30 min), the rise in plasma LH induced by NE was significantly enhanced. Preoptic ECS (0 min) evoked a rise in plasma LH and this response was also enhanced by morphine pretreatment. The major effect on LH release occurred when sc morphine injections (-15 min) were combined with MPOA-ECS (0 min) followed by icv NE (30 min). In these rats, a remarkable and highly significant release of LH occurred which reached peak levels even greater than those observed during spontaneous LH surges (2,392 versus 16 to 1,800 ng/ml). Since morphine has profound effects on the serotonergic system, in the third series of studies, morphine was infused into the dorsal raphe nucleus (DRN) and LH responses to MPOA-ECS or icv NE alone or following combined ECS + NE were examined. DRN morphine did not affect basal LH release but it produced a rapid and highly significant rise in plasma prolactin. When DRN morphine was given (-15 min) and NE was infused icv (30 min), there was marked amplification in LH release compared to those values observed after only NE. However, there were no appreciable differences in LH values obtained after sc versus DRN morphine injections in response to NE. Similarly, the amplification of LH release which occurred following DRN morphine (-15 min) + MPOA-ECS (0 min) was not different from that obtained after sc morphine. In the final group of rats, DRN morphine was given (-15 min), the preoptic area was stimulated (0 min) and NE was infused (30 min). Following this treatment, plasma LH release was also markedly enhanced and did not differ appreciably (except at 60 and 120 min) from the levels of LH released after sc morphine. Prolactin concentrations rose slowly after icv NE to reach peak levels 75 min after treatment. Combinations of morphine + MPOA-ECS without or with NE neither augmented nor suppressed the high prolactin concentrations achieved after only DRN morphine infusions. We conclude from these data that: 1) those opiate neuronal terminals which synapse directly on LHRH neurons do not affect LHRH neuronal responsiveness to either NE, to MPOA-ECS or to combined preoptic stimulation+ NE, and 2) morphine has profound effects on LHRH neuronal responsiveness to both NE, to MPOA-ECS and, in particular, to combined ECS + NE. Since amplification of LH release occurs after treatment of rats with morphine either by sc injections or DRN infusions, the augmented LH and prolactin responses observed are most likely due to the morphine-induced release of serotonin and not to direct morphine effects on LHRH neurons.     

Comparison of stress response in male and female rats: Pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone

Three potent stressors (forced running, immobilization, and footshock) were found to increase levels of cyclic AMP in the pituitaries of both female and male rats. The pituitary cyclic AMP response in females was generally similar to that observed in males.

The tested stressors elevated both plasma corticosterone and prolactin and decreased plasma growth hormone. Plasma corticosterone rose more rapidly in females than in males following stress. Control growth hormone levels were higher in male rats. There was no clear cause and effect relationship between elevations of pituitary cyclic AMP and changes in plasma levels of prolactin, corticosterone, and growth hormone.     

Plasma growth hormone and prolactin response to dopaminergic GABAmimetic and cholinergic stimulation in Huntington's disease

We studied the acute effects of pharmacologic stimulation of neurotransmitter systems implicated in growth hormone and prolactin regulation in eight patients with Huntington's disease and matched control subjects. Both apomorphine, a dopamine agonist, and muscimol, a GABA agonist, produced an exaggerated rise in plasma growth hormone levels in the Huntington patients. Neither the growth hormone response to a muscarinic agonist, arecoline, nor the prolactin response to any of these drugs differed in the patients and controls. Loss of somatostatin activity in the hypothalamic-pituitary axis in Huntington's disease could account for these endocrinologic changes.     

Failure of postictal growth hormone rise in a patient with thalamic lesions

A patient with bilateral thalamic lesions had a spontaneous generalized convulsion during nocturnal polygraphic recording. Postictal measurements of cortisol and prolactin showed the expected rise of plasma values at 30 and 60 minutes after the seizure, but growth hormone did not increase. This observation suggests that suprahypothalamic mechanisms regulating growth hormone release differ from those involved in the neural control of cortisol-ACTH and prolactin secretion. The thalamus may intervene as a regulatory center in the release of growth hormone.     

(Des-tyrosine1)-gamma-endorphin in schizophrenia: Clinical,biochemical, and hormonal aspects

The neuropeptide (des-tyrosine¹)-γ-endorphin (DTγE; β-LPH 62–77) was given to 10 schizophrenic patients who had been free of neuroleptic medication for at least 3 weeks. DTγE was injected intramuscularly in a dose of 1 mg daily for 10 days following a double-blind placebo-controlled crossover design. In 4 of the 10 patients a pronounced antipsychotic effect was observed; in 3 a temporary or slight reduction of psychotic symptoms occured; and in 3 no response was noted. DTγE led to decreased plasma levels of prolactin and in some patients to increased concentrations of homovanillic acid in cerebrospinal fluid (CSF). Neither plasma levels of growth hormone and cortisol nor CSF concentrations of 5- hydroxyindoleacetic acid were affected by DTγE. These data confirm that DTγE has antipsychotic properties in a number of schizophrenic patients and suggest an interaction between DTγE and central dopaminergic systems.