Inhibitory effects of substance P on the gamma-amino-butyric acid and gamma-hydroxybutyric acid-induced growth hormone and prolactin release in male rats

Gamma-aminobutyric acid (GABA) at 50 μg/10 μ1 was injected into the lateral ventricle after pretreatment with intraventricular injection of 1 μg of substance P in urethane anesthetized male rats. Thirty minutes after GABA injection the animals were decapitated and blood samples were collected from the trunk. Serum GH and prolactin were determined by radioimmunoassays. The intraventricular GABA elicited a significant increase in both serum GH and prolactin levels. Intraventricular substance P itself had no effect on serum GH and prolactin, but it inhibited the GABA-induced increases in serum GH and prolactin. Gamma-hydroxybutyric acid (GHB) was intraperitoneally injected with and without an intraventricular injection of substance P in urethane anesthetized rats. The GHB injection significantly increased serum GH and prolactin levels. Pretreatment with substance P completely inhibited the GHB-induced GH and prolactin responses. These results suggest that substance P might interact with GABA in the central nervous system.     

Growth hormone release inhibiting hormone: actions on thyrotrophin and prolactin secretion after thyrotrophinreleasing hormone.

The hypothalamic tetradecapeptide growth hormone release inhibiting hormone (GH-RIH) blocked the thyrotrophin response to thyrotrophin-releasing hormone (TRH) in normal people and in patients with primary hypothyroidism. This inhibition was dose related. The TRH-induced prolactin release was not affected by GH-RIH. This dissociation of the thyrotrophin and prolactin responses to TRH by GH-RIH suggests that there are different mechanisms for release of thyrotrophin and prolactin and that only the former is affected by GH-RIH.     

Analgesic activity of substance P in rats: apparent mediation by met-enkephalin release

The intracerebroventricular administration of Substance P (SP) produced a marked and short-lasting increase in the threshold for vocalization and vocalization afterdischarge in the rat after electrical stimulation of the tail. This effect was blocked by naloxone and potentiated by bacitracin, a peptidase inhibitor. The analgesic effect of SP was also blocked by the concomitant intraventricular injection of the specific antibody against the opioid peptide metenkephalin but not by the antibody against beta-endorphin. Anti-met-enkephalin did not block other pharmacological actions of SP. The results suggest that SP produces an analgesic effect in rats by releasing met-enkephalin at supra-spinal levels involved in pain control.     

The effects of opiate agonists on growth hormone and prolactin release in rats

Various opioid receptor agonists, including Met5-enkephalin amide, Leu5-enkephalin amide, [D-Ala]2-Met5-enkephalin amide, [D-Ala]2-Leu5-enkephalin amide, morphine sulfate, d-methadone hydrochloride, and l-methadone hydrochloride were administered to adult male rats by subcutaneous injection. All opioid receptor agonists except Leu5-enkephalin amide significantly stimulated growth hormone and prolactin release. Naloxone and naltrexone blocked the hormone stimulatory effects of the opioids and both naloxone and naltrexone, when administered alone, significantly reduced serum growth hormone and prolactin concentrations. The dopaminergic agonist apomorphine, but not the alpha-adrenergic agonist clonidine, blocked opiate stimulation of prolactin. Morphine sulfate caused growth hormone release in rats pretreated with alpha-methyl-p-tryosine, a catecholamine synthesis inhibitor. Cholinergic agonists, physostigmine and pilocarpine, antagonized the growth hormone and prolactin release induced by morphine sulfate. The data suggest that the opiates stimulate prolactin via an interaction with catecholaminergic neurons controlling prolactin release and stimulate growth hormone via a mechanism independent of alpha-adrenergic or general catecholaminergic influence. The mechanism through which cholinergic agonists act to inhibit opiate agonist stimulation of growth hormone is presently unknown.     

Thyroid stimulating hormone and prolactin secretion: reduced sensitivity to TRH-stimulated prolactin release after midpregnancy in rats

Prolactin (PRL) and thyroid stimulating hormone (TSH) plasma concentrations were measured during the latter part of the dark period in early and mid-late pregnancy in the rat. On Days 4-5 and 7-8 of pregnancy, plasma PRL concentrations surged between 22:00 and 06:00 hr and TSH values increased between 22:00 and 02:00 hr. While the TSH pattern was maintained during the second-half of pregnancy, surges in PRL release ceased and PRL levels remained at less than 10 ng/ml. The effects of thyrotropin releasing hormone (TRH) administration on PRL and TSH secretion were then measured to determine whether the second-half of pregnancy is associated with a decrease in sensitivity to an agent that can stimulate PRL release. Injection (iv) of cannulated pregnant rats with a low dosage (20 ng) of TRH stimulated a twofold increase in plasma TSH during both early (Days 5-9) and later (Days 14-18) pregnancy but did not change plasma PRL levels. Treatment with a high dosage (2 micrograms) of TRH induced a sixfold rise in plasma TSH during both phases of gestation. The higher dose of TRH also stimulated elevations in plasma PRL during early and mid-late pregnancy; however, both the absolute increase in the amount of PRL in plasma and the percentage increase over baseline levels were greater from Days 5-9 than from Days 14-16 of gestation. These data indicate that the neuroendocrine sensitivity to factors that stimulate PRL secretion changes as pregnancy progresses, and suggest that nocturnal secretion of PRL and TSH during pregnancy may be regulated, in part, by a common trophic factor.     

Follicle stimulating hormone and prolactin release induced by prostaglandins in rat

Ten to 60 minutes following a single i.v. injection of PGE₂ (500 μg/rat) into male rats of 30 to 35 days of age FSH concentration in the serum was raised significantly. The rise in FSH was maintained from 10 to 60 minutes after treatment, then at 90 minutes FSH had declined and was not significantly different from that of the control before treatment. Prostaglandin E₁, E₂ or F_2α (670μg/rat) significantly increased the serum prolactin level 10 to 60 minutes after a single i.v. injection in spayed rats primed with estrogen and progesterone. And, rats primed with estrogen and progesterone. And, increases in prolactin in the serum were observed with as little as 2μg of PGE₁ or E₂, and 20μg of PGF_2α. Twenty μg of PGE₂, and 200μg of PGE₁ or F_2α gave the maximum stimulation. These results indicate that release of pituitary hormones is affected by prostaglandins.Prostaglandins (PGs) are widely distributed in mammalian tissues, and they have been reported to have an almost equally wide variety of endocrine and metabolic effects. It was recently postulated that PGs may be involved in the process of ovulation because ovulation was blocked by inhibitors of PG synthesis (1–5).     

Stimulation of prolactin release in rats by GABA.

Infusion of GABA into the lateral ventricle of intact female rats on the morning of proestrus and in ovariectomized rats significantly stimulated PRL release. This response apparently is not mediated through a direct action on the pituitary since injection of GABA into hypophysectomized rats with a pituitary transplant under the kindney capsule did not alter serum prolactin levels. These observations suggest that GABA may have a role in regulating prolactin secretion.     

Opioid components of the clockwork that governs luteinizing hormone and prolactin release in male rats

Daily rhythms of secretion have been described for luteinizing hormone (LH) and prolactin (PRL) from the anterior pituitary of rats. Using selective opioid antagonists, we found that mu and kappa opioid receptor ligands regulate LH and PRL secretion and, of particular interest, that the magnitude of opioidergic effects varies with the time of day. In addition, incomplete temporal overlapping of the LH and PRL responses to the antagonists suggests that different endogenous opioid pathways, with different temporal profiles of peptide release, may control each of these hormones.     

Stimulation of prolactin release by prolactin-releasing peptide in rats.

We have previously reported a hypothalamic peptide that shows specific prolactin (PRL)-releasing activity in vitro, named prolactin-releasing peptide (PrRP). However, its activity in vivo has not yet been shown. In this study, we examined whether PrRP could induce specific PRL release in vivo using normal cycling female and male rats. Intravenous injection of PrRP31 increased plasma PRL levels in rats in a dose-dependent manner. PrRP31 (50 nmol/kg i.v.) significantly (P < 0.05) stimulated plasma PRL levels within 25 min after injection in rats in proestrus, estrus, and metestrus. A higher dose of PrRP31 (500 nmol/kg i.v.) was necessary for a significant increase in plasma PRL levels in male rats. These results clearly indicate that female rats, especially at proestrus, are more sensitive to PrRP-induced PRL secretion than male rats. The effect of PrRP on PRL release is affected considerably by the estrous cycle and sex, which suggests that PrRP sensitivity is controlled by the endogenous hormonal milieu, such as estrogen levels. PrRP31 did not affect other pituitary hormone secretions. The results indicate that PrRP shows specific PRL-releasing activity in vivo as well as in vitro and suggest that it plays an important role in the regulation of PRL release under certain physiological conditions.     

Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the third ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of substance P (SP) or neurotensin (NT) and plasma GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of physiologic saline iv or into the third ventricle did not modify plasma hormone levels. Intraventricular injection of SP or NT at doses of either 0.5 or 2 μg elevated plasma GH concentrations within 5 min and they remained elevated for 60 min. Third ventricular injection of similar doses of SP or NT had no effect on plasma TSH. An intermediate dose of 1 μg of SP or NT given iv had no effect on plasma GH but NT elevated plasma TSH. Incubation of hemipituitaries from OVX rats with varying doses of SP or NT did not alter GH release into the medium but TSH release was enhanced with NT at doses of 100 or more ng/ml of medium. It is suggested that SP acts centrally to stimulate growth hormone-releasing factor (GRF) or to inhibit somatostatin release and thereby enhance GH release and that NT acts directly on the pituitary to stimulate TSH release.     

Effect of substance P/bombesin antagonists on the release of growth hormone by GHRP and GHRH.

The substance P(SP)/bombesin (Bn) antagonists [DArg1DTrp7,9Leu11] SP(P-7482), [DArg1-DPro2DTrp7,9Leu11]SP (P-7483), [DArg1DPhe5DTrp7,9Leu11]SP(P-7492), and the growth hormone releasing hormone (GHRH) antagonist [DArg2Ala8,9,15]GHRH(1-29)(DC21-366) were tested for their in vitro effects on the release of growth hormone (GH) in the presence of GHRH and growth hormone releasing peptide, HisDTrpAlaTrpDPheLysNH2(GHRP). P-7492, P-7483, and P-7482 decreased, dose-dependently, the release of GH by GHRP (IC50 = 0.2 microM, 0.85 microM, and 6 microM, respectively). These antagonists had only a 10-15% inhibitory effect on the stimulated GH release of GHRH even at high dosage. DC21-366 decreased the stimulated release of GH by GHRH (IC50 = 0.16 microM) but not by GHRP. Neither SP nor Bn had GH releasing or inhibitory effects in this system.     

Serum luteinizing hormone follicle-stimulating hormone and prolactin in neonatal-androgenized rats.

Serum levels of LH, FSH, Prolactin and Testosterone of 90 days old male rats androgenized soon after birth were determined by specific radioimmunoassay and were compared to untreated rats. LH and FSH levels were also determined in 90 days old female rats neo-natally treated with testosterone and compared with normal diestrus rats. Androgenization of male rats significantly increased serum FSH and Prolactin levels without producing changes in plasma LH and testosterone concentrations. Similar increase in the FSH levels were found in androgenized female rats although plasma FSH concentrations were lower than in the male groups. These results obtained in male rats give an additional evidence that androgens acting in the first days of life are responsible of the higher levels of FSH and Prolactin that characterize the male or tonic pattern of gonadotrophin secretion.     

Suppression of basal and stress-induced prolactin release and stimulation of luteinizing hormone secretion by alpha-melanocyte-stimulating hormone

alpha-MSH and beta-endorphin, both synthesized from a common precursor, have opposite behavioral actions. In order to determine if these peptides have opposite effects on pituitary function, basal LH secretion and basal and stress-induced prolactin release were studied in adult male rats after intraventricular injection of alpha-MSH. Each rat also received intraventricular saline in order to serve as its own control. 18 micrograms alpha-MSH stimulated plasma LH from 16.5 +/- 2.5 (SEM) ng/ml to a peak of 27.2 +/- 4.0 and 26.0 +/- 4.9 ng/ml at 5 and 10 min, and suppressed prolactin from 3.5 +/- 0.7 ng/ml to 1.3 +/- 0.1 and 1.2 +/- 0.1 ng/ml at 15 and 30 min. Intraventricular alpha-MSH also significantly blunted the prolactin rise associated with the stress of swimming. 10 and 20 min after the onset of swimming, prolactin levels in rats pretreated with alpha-MSH were significantly diminished: 7.4 +/- 1.5 and 6.5 +/- 2.0 ng/ml vs 23.8 +/- 3.6 and 15.2 +/- 2.8 after normal saline. Similarly, des-acetyl alpha-MSH which is the predominant form of alpha-MSH in the hypothalamus, diminished the stress-induced prolactin rise from 18.4 +/- 5.3 and 11.2 +/- 3.4 ng/ml at 10 and 20 min to 10.0 +/- 2.4 and 5.5 +/- 1.6 ng/ml. We conclude that centrally administered alpha-MSH stimulates LH and suppresses basal and stress-induced prolactin release in male rats. These actions are opposite to those previously shown for beta-endorphin and suggest that alpha-MSH may antagonize the effects of beta-endorphin on pituitary function.     

Growth hormone and prolactin content of hyperplastic anterior pituitary of dehydroepiandrosterone treated rats.

30 days after implantation of 80 mg dehydroepiandrosterone (androst-5-en-3betaol-17-one) hyperplastic enlargement of the anterior pituitary has been observed in about 80 per cent of the female rats. There was an important increase of prolactin content, growth hormone content remained unchanged. The mentioned alterations were found to be reversible, since regression was observed after DEA treatment exceeding 30 days. In females developing no hyperplasia pituitary growth hormone contentration and content has been decreased, prolactin content remained unchanged. In male rats on identical treatment no change of pituitary weight, growth hormone and prolactin concent has been found. The results suggest that, under physiological conditions, DEA does not affect pituitary growth hormone and prolactin content, however response to pharmacological doses was different in male and female rats.     

Effect of Calcitonin on prolactin release in rats

Injection of [Asu^1,7]-eel calcitonin (CT) (0.1–2.5μg) into the lateral ventricle resulted in a significant and dose-related increase of plasma prolactin (PRL) levels in urethane-anesthetized male rats. Naloxone failed to block [Asu^1,7]-eel CT induced PRL release. Salmon CT, human CT and porcine CT were similarly effective to stimulate PRL release when injected intraventricularly. Intravenous administration of [Asu^1,7]-eel CT(20 μg) failed to cause any significant changes in plasma PRL levels, while this peptide (10^?8?10^?6M) possesed a mild stimulating activity of PRL release from the anterior pituitary cells cultured $\text{in vitro}$. These results suggest that CT stimulates rat PRL secretion mainly through the central nervous system like one of the neurotransmitters, though it may also act directly on the pituitary.     

Various proteinase inhibitors decrease prolactin and growth hormone release by anterior pituitary cells

Proteinase inhibitors were tested for their ability to inhibit prolactin (PRL) and growth hormone (GH) release by cultured anterior pituitary cells of the rat. Inhibitors of microbial origin (chymostatin, elastatinal, leupeptin) had either no or a moderate effect on hormone release while some tripeptide aldehydes, especially those with lysine at their C terminus, inhibited markedly PRL and to a lesser extent GH release. Boc-DPhe-Phe-lysinal was the most effective on lactotrophs inhibiting PRL release more than 50% at 10(-4) M. The site(s) of action of tripeptide aldehydes remain to be elucidated.     

Growth hormone and prolactin secretion after hypothalamic deafferentation in pigs

Control of growth hormone (GH) and prolactin (PRL) secretion was investigated in ovariectomized, prepuberal Yorkshire gilts by comparing the effects of anterior (AHD), complete (CHD), and posterior (PHD) hypothalamic deafferentation with sham-operated controls (SOC). Blood samples were collected sequentially via an indwelling jugular catheter at 20-min intervals during surgery and recovery from anesthesia (Day 0) and Days 1 and 2 after cranial surgery. Mean serum concentrations of GH after AHD, CHD, and PHD were reduced (P less than 0.01) when compared with SOC gilts. Furthermore, episodic GH release evident in SOC animals was obliterated after hypothalamic deafferentation. PRL concentrations in peripheral serum of hypothalamic deafferentated gilts remained similar (P greater than 0.05) to those of SOC animals. These results indicate that anterior and posterior hypothalamic neural pathways play a minor role in the control of PRL secretion in the pig in as much as PRL levels remained unchanged after hypothalamic deafferentation. These findings may be interpreted to suggest that the hypothalamus by itself seems able to maintain tonic inhibition of PRL release. In contrast, the maintenance of episodic GH secretion depends upon its neural connections traversing the anterior and posterior aspects of the hypothalamus in the pig.