Role of central nervous system neurotransmitters in mediating the effects of morphine on growth hormone-and prolactin-secretion in the rat

Unanesthetized adult male rats with indwelling right atrial cannulae were used in the majority of experiments. Morphine (MOR, 3.0 mg/kg) caused a large but transient increase in both GH and PRL levels, which could be prevented with naloxone. Disruption of central noradrenergic function with diethyldithiocarbamate (400 mg/kg) or phenoxybenzamine (15 mg/kg) abolished the GH-releasing effect of MOR, without interfering with the PRL secretory response. Depletion of brain serotonin stores with p-chlorophenylalanine (300 mg/kg) or 5,7-dihydroxytryptamine or administration of serotonin receptor blocker, cyproheptadine (2.5 mg/kg), did not diminish the GH respnse to MOR but it inhibited, or in the case of 5,7-DHT treatment abolished the activation of PRL secretion. Additionally, metergoline (0.1 and 1.0 mg/kg), another serotonin receptor blocker, caused an inhibition of the GH-releasing action of MOR; however, this inhibition was reversed by pretreatment with spiroperidol (0.1 mg/kg). Metergoline also markedly diminished the MOR-induced elevation of PRL. Inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha-MT, 250 mg/kg) blunted the effect of MOR on GH; however, dopamine receptor blockers, spiroperidol (0.01 and 0.1 mg/kg) or (+)butaclamol (0.3 and 1.3 mg/kg), were without any influence. alpha-MT or spiroperidol did not alter the effect of MOR on PRL secretion, but the higher dose of (+)butaclamol suppressed it. It is concluded that the GH-releasing action of MOR requires unimpaired functioning of the central noradrenergic system, while the serotonergic and dopaminergic systems appear to play no significant role in it. In contrast, serotonergic systems seem to be essential for the activation of PRL secretion, whereas the noradrenergic system is not involved. It remains uncertain whether morphine activtes PRL secretion also through inhibition of dopaminergic activity. We favor the view that the dopaminergic component participates in the PRL activation by MOR, but that its contribution to the overall effect is rather small.     

Monosodium glutamate: Acute and chronic effects on rhythmic growth hormone and prolactin secretion, and somatostatin in the undisturbed male rat

The present investigation was designed to determine the chronic effects of neonatal monosodium glutamate (MSG) administration (4 g/kg s.c.) and the acute effects of MSG (1 g/kg i.p.) on episodic growth hormone (GH) and prolactin (PRL) secretion and brain somatostatin (SRIF) in unanesthetized, chronically cannulated male rats.Adult rats showed the typical physical characteristics that result from neonatal MSG administration. Analysis of episodic GH secretion showed a significant reduction in: (1) the amplitude of GH secretory peaks; and (2) the mean 5.5-h plasma level of GH. Bursts of plasma PRL were inhibited by MSG, but the mean 5.5-h plasma levels were not affected. SRIF concentrations in the medial basal hypothalamus were reduced by 60% after neonatal MSG. Acute administration of MSG to adult rats caused an immediate, long-lasting suppression of rhythmic GH secretion and a rapid, transient release of PRL.These results suggest: (1) neonatally administered MSG causes a marked disturbance in episodic GH and PRL secretion in adult rats; (2) MSG induces a decrease in hypothalamic SRIF and possibly GH-releasing factor; and (3) the acute effects of MSG on GH and PRL may be due to the inhibition and/or excitation of a complex neuronal network involving monoaminergic and peptidergic systems.     

Acute and chronic morphine modifies the in vivo release of methionine enkephalin-like immunoreactivity from the cat spinal cord and brain

The effect of acute and chronic morphine treatment was investigated on the spontaneous and evoked release of methionine enkephalin-like immunoreactivity (MELI) in vivo using the technique of cat spinal superfusion and ventriculocisternal perfusion. Stimulation of sciatic nerve, at intensities known to activate small-diameter nerve fibers, resulted in a consistent release of MELI from the spinal cord and the brain. Local application of morphine (5 X 10(-4)M) to the spinal cord resulted in a significant decrease in the evoked release of MELI. Naloxone (2 mg/kg i.v.), administered during morphine treatment, produced an increase in the spontaneous and greatly augmented the evoked release of spinal and ventricular MELI. In morphine-naive animals, naloxone did not affect the spontaneous or evoked MELI release. In cats chronically exposed to parenteral morphine by implantation of morphine pellets (2 X 75 mg), the spontaneous release of spinal and ventricular MELI was significantly greater than this release in control animals. Stimulation of sciatic nerves evoked a normal release of MELI in morphine-pelleted animals. Administration of naloxone to these animals resulted in a large and sustained increase in the spontaneous release of MELI from the spinal cord and brain. The material released by stimulation was identified as methionine enkephalin-like on the basis of similar results with two different antisera, parallel displacement curves with serial dilutions of spinal and ventricular perfusates and comigration with methionine enkephalin on a Sephadex G-25 column. These results suggest that if there is a tonic suppression of enkephalin release mediated by opiate receptors, these receptors display a tolerance development also. The facilitated release by naloxone in the chronic morphine-treated animals may indicate that reversal of the ongoing opioid inhibition results either in an excessive drive of the enkephalinergic neuron by other excitatory systems or the loss of a tonic auto-inhibition, which is not present in the non-tolerant animal.     

Effects of morphine on luteinizing hormone secretion and catecholamine turnover in the hypothalamus of estrogen-treated rats

This study examined the effects of morphine sulfate and naloxone alone or in combination on phasic luteinizing hormone (LH) secretion in estrogen-treated ovariectomized rats. Thereafter, the effects of morphine on initial concentrations, rate constants and rates of turnovers of norepinephrine and dopamine were evaluated in untreated or morphine-injected, estrogen-primed rats. Morphine, when given at 12.30 h, completely suppressed the spontaneous LH surges which occur in steroid-treated rats. The opiate antagonist, naloxone, (12.15 h) markedly amplified and advanced the time of LH release and a combination of morphine and naloxone produced peak afternoon LH values which were intermediate between those obtained in controls and in rats receiving only naloxone. Norepinephrine (NE) and dopamine (DA) turnover were calculated from data obtained in groups of rats sacrificed 0,45 or 90 min after administering 300 mg/kg b. wt. i.p. ofα-methyl-p-tyrosine (α-MPT) at 10.00 or 15.00 h. In these experiments, the medial preoptic nucleus (MPN) and the median eminence (ME) were microdissected and analyzed for changes in NE and DA concentrations by a radioenzymatic procedure. In estrogen-treated rats, NE rate constants and turnover significantly increased at 15.00 vs 10.00 h in MPN and ME concomitant with increases in serum LH. Morphine blocked both increases in rate constants and turnover in the MPN and ME and also significantly reduced initial concentrations of NE in the MPN. None of the DA parameters measured in MPN or ME changed in estrogen-treated controls between morning and afternoon. Further, while morphine did not affect DA turnover in the MPN, DA turnover declined in the ME. These data add to accumulating evidence which demonstrates an important modulatory role for hypothalamic opiate neurons in regulating catecholamine activity and gonadotropin secretion.     

Striatal lesions change the behavioral effects of morphine in cats

Cats injected with a relatively low single dose of morphine sulfate (0.5–3.0 mg/kg i.p.) exhibit a long-lasting group of behaviors which we quantified via a time-sampling video technique. The dominant events are complex head movements accompanied by discrete paw, ear and body movements with the animal in a quiet posture, all of which appeared to be visually mediated. Cats with extensive lesions of the caudate nuclei do not show this profile; instead they show unspecific locomotor activity proportional to the size of the ablation and to the dose of morphine. These effects are blocked by naloxone in both intact and lesioned animals. The robustness of these results indicate that (i) the striatum is involved in the behavioral effects of morphine, and (ii) that the cat is a useful, sensitive model for the study of the behavioral effects of opiates.     

Clonidine-induced growth hormone secretion in chronic schizophrenia

Clonidine (0.15 mg intravenously), an alpha-adrenergic receptor agonist, was administered to 13 male chronic schizophrenics, who had been withdrawn from chronic neuroleptic therapy, and to 18 normal male controls. There was no significant difference in growth hormone (GH) response between the two groups. There was no significant correlation between duration of psychosis, duration of neuroleptic therapy or length of neuroleptic withdrawal and GH response. These results suggest that postsynaptic alpha-adrenergic receptor function in the hypothalamic-pituitary axis is unaltered in chronic schizophrenia or by prior chronic neuroleptic therapy.     

Effect of dopamine and neuroleptics on plasma growth hormone and prolactin in normal men

(1) This study investigates further the locus of action of dopamine (DA) and DA antagonists in affecting growth hormone (GH) and prolactin (PRL) secretion in normal subjects. (2) Each of three normal men was tested twice with a continuous DA infusion (0.3 mg/min) over 90 min. (3) Mean plasma GH concentration was significantly (p < 0.05) elevated above baseline at 30 min after onset of DA infusion. (4) The same subjects were also tested twice with the identical dose of a DA infusion after a single neuroleptic drug had been given i.v. 30 min earlier. This pretreatment with an antidopaminergic drug resulted in a significant delay and attenuation of the GH response to DA. (5) The elevated plasma PRL concentration induced by the neuroleptic was suppressed to baseline within 60 min after onset of the DA infusion. (6) Since DA does not cross the blood brain barrier (BBB) these findings indicate that GH secretion can be affected in normal men by dopaminergic mechanisms operating outside the BBB.     

Changes in anterior pituitary hormone secretion and hypothalamic catecholamine metabolism during morphine withdrawal in the female rat

Studies were undertaken to evaluate the acute responses of hypothalamic noradrenergic and dopaminergic neurons and anterior pituitary hormones to naloxone (NAL)-precipitated morphine (MOR) withdrawal in the rat. Ovariectomized female rats were rendered MOR-dependent and injected with NAL (1 mg/kg b.w., s.c.). During precipitated MOR withdrawal, a decline in norepinephrine (NE) concentrations was preceded by an increase in the level of its metabolite normetanephrine (NME) in the medial basal hypothalamus (MBH) as well as the preoptic area-anterior hypothalamus (POA-AH). Both dopamine (DA) and its major acid metabolite, dihydroxyphenylacetic acid (DOPAC), showed increased concentrations in these two hypothalamic regions within 30 min of NAL administration. Elevated luteinizing hormone (LH) and beta-endorphin secretion was evident within 5 min of NAL injection to MOR-dependent rats, while serum prolactin (PRL) increased 15 min into MOR withdrawal. Both growth hormone (GH) and thyroid-stimulating hormone (TSH) were depressed over the course of MOR withdrawal. Although a cause and effect relationship cannot be established, during NAL-precipitated MOR withdrawal, a heightened hypothalamic monoaminergic neuronal activity is accompanied by a differential response of anterior pituitary hormones. The observed responses, which are similar to those seen during acute stress, indicate that MOR withdrawal may activate the same mechanisms which mediate the neuroendocrine response to stress.     

Depressant and excitant effects of intraspinal microinjections of morphine and methionine-enkephalin in the cat

The effects of intraspinal microinjectins of morphine (10 microgram) and methionine-enkephalin (Met-enkephalin) (5 microgram) on the C-fiber and polysynaptic reflexes in the acute decerebrate low spinal cat were investigated. Microinjected into the dorsal horn, morphine and Met-enkephalin depressed the nociceptive C-fiber reflex (CFR) without altering the short latency polysynaptic reflex. Microinjected into the ventral horn, morphine and Met-enkephalin facilitated the C-fiber and polysynaptic reflexes. Pretreatment of the cats with intravenous naltrexone (2 mg/kg) antagonized the depressant effects produced by dorsal horn intraspinal microinjections of morphine and Met-enkephalin. The excitant effects of ventral horn microinjections of morphine were not antagonized by naltrexone (2 mg/kg). These results support a hypothesis that the analgesic effects of morphine at the spinal cord level are due to interactions with opiate receptors in the dorsal horn.     

Anatomically specific changes in the expression of somatostatin, growth hormone-releasing hormone and growth hormone receptor mRNA in diabetic rats

Growth hormone (GH) secretion is altered in poorly controlled diabetic animals. However, modifications in the hypothalamic neuropeptides that control GH secretion, somatostatin and GH-releasing hormone (GHRH), as well as changes in the sensitivity of the hypothalamus and pituitary to the feedback effects of GH, are less clear. We have used RNase protection assays and in-situ hybridization to address whether the mRNA expression of GH, somatostatin and GHRH, as well as of the GH receptor (GHR) in the hypothalamus and anterior pituitary, are altered in streptozotocin-induced diabetic rats. After induction of diabetes, rats were treated with insulin twice daily for 3 weeks to obtain either poorly controlled (mean plasma glucose >300 mg/dl) or well-controlled diabetic rats. Although no significant change in pituitary GH mRNA expression was found, the hypothalamic expression of GHRH and somatostatin mRNA was reduced in poorly-controlled diabetic rats and returned to control values with normalisation of plasma glucose concentrations (P<0.0001 and P<0.002, respectively). Somatostatin mRNA expression was reduced only in the central portion of the periventricular nucleus, with no change being seen in the other areas of the periventricular nucleus or in the arcuate, suprachiasmatic or paraventricular nuclei. A significant decline in GHRH mRNA expression was observed in both the arcuate nucleus and ventromedial hypothalamus. Anterior pituitary GHR mRNA expression was significantly reduced in both well and poorly-controlled diabetic rats, while there was no change in the hypothalamus. To examine whether the evolution time of the diabetes influences these parameters, in a subsequent experiment, diabetic rats received no insulin for 2 months. A significant decline in GHRH and somatostatin mRNA expression was also observed in these rats. In addition, pituitary GH mRNA expression declined significantly in long-term diabetic rats. These results demonstrate that: (1) the expression of both GHRH and somatostatin declines specifically in anatomical areas involved in anterior pituitary hormone control; (2) GHR mRNA expression is decreased in the pituitary of diabetic rats, but not in the hypothalamus, and does not return to control values with normalisation of mean blood glucose concentrations; and (3) the evolution time of the diabetes is important for detecting some changes, including the decrease in pituitary GH mRNA expression.     

Effect of enhancement of cholinergic tone on the growth hormone response to acute hyperglycaemia or thyrotropin-releasing hormone in dogs

The effect of enhancement of cholinergic tone by pyridostigmine on the growth hormone (GH) response to thyrotropin-releasing hormone (TRH) or glucose-induced acute hyperglycaemia was tested in six adult unanaesthetized beagle dogs. Both TRH (5μg/ kg iv) and glucose (2 g/kg orally) did not significantly alter baseline GH levels but reduced the GH response to GH-releasing hormone (GHRH) (2 μg/kg iv), although this effect was more clear-cut with TRH than with glucose. Pretreatment with pyridostigmine (2 mg/kg orally) counteracted the inhibitory effect of hyperglycaemia on the GHRH-induced GH release, but had no effect on the inhibition induced by TRH. In summary, these results indicate that: 1) acute hyperglycaemia and TRH play an inhibitory role on GHRH-stimulated GH secretion in dogs; 2) the inhibitory effect of acute hyperglycaemia is mediated via hypothalamic cholinergic neurotransmission, whereas other neurotransmitter pathways would be. involved in the effect of TRH.     

Effect of hypthalamic ventromedial lesions on plasma growth hormone response to growth hormone-releasing factor in rats

The effect of ventromedial-arcuate (VMH-ARC) nuclei lesions on plasma growth hormone (GH) response to human growth hormone-releasing factor (GRF, 1 μg/kg b.wt., i.v.) was studied in conscious rats after they had received chlorpromazine (CPZ) or CPZ plus antiserum against somatostatin (ASS). When rats were pretreated with CPZ alone, there was no difference in basal plasma GH level between VMH-ARC lesioned rats and controls. The magnitude of plasma GH response to GRF in 5 out of 6 VMH-ARC lesioned rats exceeded that of controls. When the same observation was repeated using the same rats after they had received ASS and CPZ, basal plasma GH levels of controls were significantly higher than those of VMH-ARC lesioned rats, and the magnitude of the plasma GH response to GRF was augmented in both groups of rats. The plasma GH response to GRF was comparable between two groups, though the peak plasma GH response to GRF was slightly but significantly lower in VMH-ARC lesioned rats as compared to controls. Pituitary GH content was reduced significantly in VMH-ARC lesioned rats as compared to controls. The results demonstrate that the pituitary responsiveness to GRF does not appear to be altered significantly in rats bearing bilateral VMH-ARC lesions. In addition, the placement of electrolytic lesions in VMH-ARC regions causes reduced SS secretion into the hypophyseal portal vessels and leads to an augmentation of plasma GH response to GRF.     

Dextro- and L-amphetamine are equipotent in releasing human growth hormone

(1) Peak plasma human growth hormone (HGH) response to a single intravenous administration of d- and l-amphetamine sulfate 0.1 mg/kg was evaluated in ten healthy subjects each being his own control. (2) No statistical difference was found between the mean HGH responses of the subjects to either amphetamine isomer. Also, the number of deficient HGH responses to d- and l-amphetamine was equal. (3) By analogy with similar data from studies in monkeys, the involvement of noradrenergic rather than dopaminergic mechanisms in mediating amphetamine-induced HGH release in man is tentatively suggested and possible implications for recent neuroendocrinological findings in endogenous depressives are discussed.     

Effect of morphine on the cat middle cerebral artery

Morphine (up to 3 X 10(-4) M) elicited concentration-dependent contractions in cat middle cerebral arteries, higher concentrations induced vasodilation. These responses were annulled in the presence of 1-methyl-3-isobutylxanthine, but unaffected by diphenhydramine, cimetidine, phentolamine or naloxone. Ca2+ suppression blocked the morphine-evoked contractions and Ca2+ addition antagonized its vasodilatory effects. Nifedipine induced a marked relaxation in arteries previously contracted with morphine. Preincubation with nifedipine induced a decrease in the contraction elicited by morphine while it increased the vasodilatory phase. Morphine did not produce a significant effect in femoral arteries. In cerebral arteries previously submitted to an active tone, the opioid-induced vasodilation was unchanged by naloxone, cimetidine, diphenhydramine or ouabain, whereas Ca2+ addition antagonized this effect. These results indicate: that the opioid effects are mediated neither by opiate receptors nor by noradrenaline or histamine release; and that an antagonism exists between Ca2+ and the vasodilation caused by morphine.     

抑郁症患者血浆生长激素水平变化及临床意义

目的:探讨血浆生长激素(GH)水平与抑郁症之间的关系.方法:采用汉密尔顿抑郁量表对30例抑郁症患者及30例正常对照者进行评定,并采用酶联免疫吸附法测定患者和正常对照者的血浆GH水平.结果:抑郁症患者血浆生长激素水平[(7.2±1.3)ng/ml]显著高于对照组[(1.3±0.7)ng/ml],(t=21.830,P<0...     

Failure of chronic antidepressant treatment to alter growth hormone response to clonidine

The effect of 4 to 6 weeks of treatment with the antidepressants, desmethylimipramine and amitriptyline, on the growth hormone response to clinidine was studied in 12 depressed patients. In contrast to the reported effects of clonidine in healthy subjects, clonidine did not significantly increase growth hormone secretion in the depressed patients before treatment. The antidepressant treatments did not alter the growth hormone response to clonidine in either treatment responders or nonresponders.     

Electroconvulsive therapy (ECT) increases plasma growth hormone, prolactin, luteinising hormone and follicle-stimulating hormone but not thyrotropin or substance P

(1) Using radioimmunoassay, plasma levels of pituitary hormones and substance P were measured during the first 30 min after ECT in 28 sets of peripheral blood samples obtained from 21 patients (14 males and seven females) treated with ECT for endogenous depression. (2) The earliest increase was in plasma growth hormone and follicle-stimulating hormone occurring 5–14 min after ECT, followed by increases in plasma prolactin and luteinising hormone, 15–24 min after ECT. At 25–35 min after ECT only the increase in plasma growth hormone was still significant. (3) ECT had no effect on plasma levels of thyrotrophin or substance P. (4) It is suggested that the observed changes in peripheral levels of pituitary hormones are compatible with non-specific stimulation of the hypothalamo-pituitary system due to the acute stress of ECT or anesthesia.     

Amitriptyline-induced suppression of growth hormone in acromegaly

(1) Amitriptyline (100 mg p.o. daily at bedtime) for 1 month significantly reduced 24 hr mean serum growth hormone in 3 of 5 acromegalic subjects studied (44, 22 and 18% reductions). (2) Amitriptyline-induced suppression of growth hormone occurred primarily in the late afternoon and evening. (3) Amitriptyline delayed the nocturnal rise in serum growth hormone. (4) The clinical usefulness of amitriptyline in treating acromegaly would probably be very limited because of the modest nature of the reductions in serum growth hormone.     

Acute morphine treatment and morphine tolerance/dependence alter immunoreactive oxytocin levels in the mouse hippocampus

Immunoreactive oxytocin levels were measured in the mouse hippocampal tissue (h-OXT). Acute morphine treatment increased h-OXT, which effect was reversed by naloxone. In mice rendered tolerant to and dependent on morphine h-OXT was lower than in placebo pellet-implanted control mice. In the tolerant/dependent animals naloxone resulted in precipitated withdrawal syndrome which was associated with a slight increase in h-OXT. The data indicate that h-OXT is affected by acute morphine treatment and by morphine tolerance/dependence and raises the possibility that h-OXT participates in the adaptive response of the organism towards narcotic drugs.     

Growth hormone releasing factor increases growth hormone release from MtTW15 pituitary tumors

The MtTW15 pituitary tumor secretes growth hormone and prolactin. Perifusion of these dispersed MtTW15 tumor cells with 10 nM growth hormone releasing factor (GRF) increases growth hormone release without affecting prolactin release. This effect is dose-dependent between 0.001 and 0.1 nM and is blocked by 100 nM somatostatin. These findings suggest that this tumor and clones derived from it may be valuable tools in studying the cellular mechanisms of action of GRF and somatostatin.