RPEP-00032 · 1985Normal thymosin alpha 1 levels were similar across all groups of women tested, regardless of their hormonal status. This peptide appears unaffected by estrogen.
Thymosin beta 4 told a different story. Castrated women not receiving estrogen had reduced levels. Postmenopausal women on chronic estrogen therapy had even lower thymosin beta 4. Castrated women on estrogen also showed decreased levels.
Normal women in the early follicular phase (low estrogen point of the menstrual cycle), women with premature ovarian failure, and postmenopausal women not on estrogen all had similar thymosin beta 4 levels. But the premature ovarian failure and postmenopausal groups showed wide variation, suggesting these are not uniform populations.
Suh, B Y; Naylor, P H; Goldstein, A L; Rebar, R W · Cross Sectional
RPEP-00046 · 1987All four tested opioid peptides (beta-endorphin, dynorphin, MEAP, and DADLE) increased plasma corticosterone (a stress hormone) in normal rats. The effects were dose-dependent and blocked by naloxone, confirming they work through opioid receptors.
Cross-tolerance experiments revealed which receptor each peptide uses. Rats made tolerant to one opioid were tested with others. Dynorphin(1-13) and MEAP (Met-Enk-Arg-Phe) acted at kappa-opioid receptors. The synthetic peptide DADLE acted at delta-opioid receptors.
Beta-endorphin was the surprise. It did not fit neatly into the mu, delta, or kappa categories. Its corticosterone-releasing effect was maintained even in rats tolerant to all three receptor types. The researchers proposed it acts at an epsilon-opioid receptor, a debated fourth receptor type.
Iyengar, S; Kim, H S; Wood, P L · Animal Study
RPEP-00049 · 1987Beta-endorphin (0.5 microgram injected into the brain), dynorphin (1 microgram), and U50-488H (a kappa opioid drug, 10 mg/kg) all stimulated prolactin (PRL) release more in the afternoon (4-5 PM) than in the morning (8-9 AM).
Morphine (10 mg/kg subcutaneous), met-enkephalin (200 micrograms), and D-Met-Pro-Enk (0.5 microgram) did not show this daily rhythm. Their prolactin response was the same regardless of time.
For corticosterone (a stress hormone), the pattern was different. Morphine, D-Met-Pro-Enk, met-enkephalin, and dynorphin could only increase corticosterone in the morning, when baseline levels were low. In the afternoon, when baseline corticosterone was already high, there was no room for further increase.
Removing the adrenal glands eliminated the circadian rhythm in prolactin responses, suggesting that natural cortisol cycling drives the time-of-day differences.
Kiem, D T; Kanyicska, B; Stark, E; Fekete, M I · Animal Study
RPEP-00060 · 1987Thymosin alpha-1 and lymphokine-containing supernatants directly stimulated both basal and corticotropin-induced corticosterone secretion from adrenal cells.
Torres-Alemán, I; Rejas, M T; Barasoaín, I; Borrell, J; Guaza, C · In Vitro
RPEP-00077 · 1988Cortisol at 25 mg/kg given 24 hours before testing decreased prolactin release triggered by all four opioid peptides (dynorphin, beta-endorphin, met-enkephalin, D-Met-Pro-enkephalinamide) injected into the brain.
Actinomycin D pretreatment blocked cortisol's inhibitory effect. This means cortisol works by triggering new protein synthesis, not by directly blocking opioid receptors.
In adrenalectomized (no adrenal glands) rats, cortisol's inhibitory effect was even stronger. Maximum inhibition was reached at only 5 mg/kg, lower than the 25 mg/kg used in intact rats.
Cortisol did not affect opioid-induced corticosterone release. This selectivity means cortisol specifically targets the prolactin pathway, not all opioid effects.
Kiem, D T; Kanyicska, B; Stark, E; Fekete, M I · Animal Study
RPEP-00083 · 1988Alpha-helical CRF9-41 (a CRF receptor blocker) applied to hypothalamic slices in vitro caused beta-endorphin and met-enkephalin to drop significantly within 10 minutes. At the same time, LHRH (luteinizing hormone-releasing hormone) rose significantly.
Dynorphin also decreased but the change was not statistically significant.
When the antagonist was removed, the pattern reversed within 10 minutes: beta-endorphin, met-enkephalin, and dynorphin rose back up while LHRH fell back down.
The same results were obtained in vivo using push-pull perfusion of the arcuate-median eminence region in anesthetized rats. This confirmed the in vitro findings in living animals.
Nikolarakis, K E; Almeida, O F; Sirinathsinghji, D J; Herz, A · Animal Study
RPEP-00188 · 1991Glucocorticoid receptors were found in opioid peptide neurons and other peptidergic neurons, with strong regional variation across the brain.
Cintra, A; Fuxe, K; Solfrini, V; Agnati, L F; Tinner, B; Wikström, A C; Staines, W; Okret, S; Gustafsson, J A · Animal Study
RPEP-00194 · 1991Mu receptor agonists raised blood glucose and corticosterone. Delta agonist raised fatty acids only. Kappa agonist raised glucose only. Mu antagonist blocked the glucose/corticosterone effects.
Gunion, M W; Rosenthal, M J; Morley, J E; Miller, S; Zib, B; Butler, B; Moore, R D · Animal Study
RPEP-00198 · 1991Beta-endorphin inhibited POMC mRNA by 65% via delta receptors. Enkephalins also worked through delta receptors. Dynorphin worked through kappa. Mu receptors were not involved.
l'Héreault, S; Barden, N · Animal Study
RPEP-00211 · 1991Pregnancy and DES treatment altered pituitary met-enkephalin and dynorphin content in patterns paralleling oxytocin and vasopressin changes.
Schriefer, J A · Animal Study
RPEP-00212 · 1991Chronic inflammation increased basal enkephalin release but abolished CRF-stimulated release of all three opioid peptides from the hypothalamus. KCl-stimulated release remained intact.
Shippenberg, T S; Herz, A; Nikolarakis, K · Animal Study
RPEP-00221 · 1992Adrenalectomy and castration independently and interactively regulated hypothalamic CRH mRNA, CRH peptide, opioid peptide content, and CRF-stimulated opioid release.
Almeida, O F; Hassan, A H; Harbuz, M S; Linton, E A; Lightman, S L · Animal Study
RPEP-00230 · 1992Electron microscopy demonstrated direct contact between opioid peptide-containing terminals and tyrosine hydroxylase-positive (dopaminergic) cell bodies in the rat hypothalamus.
Fitzsimmons, M D; Olschowka, J A; Wiegand, S J; Hoffman, G E · Animal Study
RPEP-00255 · 1992Thymosin beta 4 peaked early and declined with age. hCG challenge depressed thymosin beta 4. Testosterone modulated both thymosin beta 4 and alpha 1 levels. Castration altered the patterns.
Wise, T H · Animal Study
RPEP-00256 · 1993CRF fibers terminate within the hypothalamus and directly modulate the release of growth hormone, gonadotropins, and opioid peptides through local synaptic connections.
Almeida, O F; Hassan, A H; Holsboer, F · Review
RPEP-00264 · 1993L-692,429 (0.001-1.0 mg/kg IV) produced dose-dependent GH release in healthy young men. At 1 mg/kg, response was comparable to GHRH-(1-29). Safe and well tolerated.
Gertz, B J; Barrett, J S; Eisenhandler, R; Krupa, D A; Wittreich, J M; Seibold, J R; Schneider, S H · RCT
RPEP-00284 · 1993Big dynorphin (prodynorphin 209-240) caused a 5.1-fold increase in serum prolactin in turkeys, mediated through kappa opioid receptors.
Youngren, O M; Silsby, J L; Phillips, R E; el Halawani, M E · Animal Study
RPEP-00288 · 1994Hexarelin effectively stimulated growth hormone secretion in both infant and adult rats through a non-GHRH pathway.
Deghenghi, R; Cananzi, M M; Torsello, A; Battisti, C; Muller, E E; Locatelli, V · Animal Study
RPEP-00295 · 1994L-692,585 produced 4.3 to 7-fold increases in peak GH with maintained efficacy over 15 days of daily dosing and elevated IGF-1 by day 15.
Jacks, T; Hickey, G; Judith, F; Taylor, J; Chen, H; Krupa, D; Feeney, W; Schoen, W; Ok, D; Fisher, M · Animal Study
RPEP-00308 · 1994Each opioid precursor family has a distinct role in the pituitary: beta-endorphin as a hormone, dynorphin as a paracrine modulator of oxytocin, and enkephalins as yet-uncharacterized players.
Schäfer, M K; Martin, R · Review
RPEP-00319 · 1995Both GHRP-6 and non-peptide GH secretagogues activated Fos expression in the arcuate nucleus and excited arcuate neuroendocrine neurons, confirming central brain actions.
Dickson, S L; Leng, G; Dyball, R E; Smith, R G · Animal Study
RPEP-00324 · 1995One month of GH replacement increased CSF GH and IGF-1 while altering monoamine metabolites, neuropeptides, and opioid peptide concentrations.
Johansson, J O; Larson, G; Andersson, M; Elmgren, A; Hynsjö, L; Lindahl, A; Lundberg, P A; Isaksson, O G; Lindstedt, S; Bengtsson, B A · RCT
RPEP-00328 · 1995Anesthesia triggered release of endogenous opioids, ACTH, vasopressin, cortisol, and catecholamines, with constant higher halothane producing more cardiovascular depression.
Luna, S P; Taylor, P M · Animal Study
RPEP-00331 · 1995Novel backbone-modified GH secretagogues with molecular weight under 500 were the most potent reported, with confirmed anabolic efficacy and a defined bioactive conformation.
McDowell, R S; Elias, K A; Stanley, M S; Burdick, D J; Burnier, J P; Chan, K S; Fairbrother, W J; Hammonds, R G; Ingle, G S; Jacobsen, N E; Mortensen, D L; Rawson, T E; Won, W B; Clark, R G; Somers, T C · Animal Study
RPEP-00339 · 1995MK-0677 was characterized as the most potent orally active GH secretagogue, with EC50 of 1.3 nM in vitro, oral efficacy in dogs at 0.125 mg/kg, and confirmed anabolic effects in rodents.
Patchett, A A; Nargund, R P; Tata, J R; Chen, M H; Barakat, K J; Johnston, D B; Cheng, K; Chan, W W; Butler, B; Hickey, G · Animal Study
RPEP-00348 · 1995IGF-1 had a half-life of only 2 minutes in the duodenum and ileum, but casein protein significantly protected it from degradation in the gut.
Xian, C J; Shoubridge, C A; Read, L C · Animal Study
RPEP-00353 · 1996GHRPs stimulate growth hormone release through a receptor distinct from GHRH, acting at both the pituitary and hypothalamic level, with consistent effects demonstrated across species and administration routes.
Argente, J; García-Segura, L M; Pozo, J; Chowen, J A · Review
RPEP-00357 · 1996Daily oral MK-677 significantly stimulated the GH-IGF-1 axis in healthy elderly adults aged 64-81, raising levels toward those seen in younger individuals.
Chapman, I M; Bach, M A; Van Cauter, E; Farmer, M; Krupa, D; Taylor, A M; Schilling, L M; Cole, K Y; Skiles, E H; Pezzoli, S S; Hartman, M L; Veldhuis, J D; Gormley, G J; Thorner, M O · RCT
RPEP-00358 · 1996Bedtime MK-677 at 25 mg for 7 days significantly increased 24-hour GH profiles and IGF-1 in young men without altering adrenocortical function.
Copinschi, G; Van Onderbergen, A; L'Hermite-Balériaux, M; Mendel, C M; Caufriez, A; Leproult, R; Bolognese, J A; De Smet, M; Thorner, M O; Van Cauter, E · RCT
RPEP-00368 · 1996KP-102 induces c-fos expression specifically in the arcuate nucleus, and this occurs even in hypophysectomized rats, confirming a direct hypothalamic site of action.
Kamegai, J; Hasegawa, O; Minami, S; Sugihara, H; Wakabayashi, I · Animal Study
RPEP-00370 · 1996Hexarelin maintained GH-releasing efficacy with repeated administration, and hexarelin plus GHRH produced a synergistic GH response exceeding individual effects.
Massoud, A F; Hindmarsh, P C; Matthews, D R; Brook, C G · RCT
RPEP-00386 · 1996GH secretagogues act through a novel receptor at dual sites (hypothalamus and pituitary) to amplify natural pulsatile GH release rather than creating continuous artificial elevation.
Smith, R G; Pong, S S; Hickey, G; Jacks, T; Cheng, K; Leonard, R; Cohen, C J; Arena, J P; Chang, C H; Drisko, J; Wyvratt, M; Fisher, M; Nargund, R; Patchett, A · Review
RPEP-00391 · 1996GHRP-2 maintained GH-releasing efficacy in critically ill patients despite blunted responses to GHRH, suggesting a preserved alternative pathway for GH stimulation.
Van den Berghe, G; de Zegher, F; Bowers, C Y; Wouters, P; Muller, P; Soetens, F; Vlasselaers, D; Schetz, M; Verwaest, C; Lauwers, P; Bouillon, R · RCT
RPEP-00395 · 1996GHRP-2 increased intracellular cAMP (like GHRH) while GHRP-6 released GH without raising cAMP, revealing partially different mechanisms despite similar GH-releasing outcomes.
Wu, D; Chen, C; Zhang, J; Bowers, C Y; Clarke, I J · In Vitro
RPEP-00397 · 1997GHRP-2 and hexarelin both showed potent GH-releasing activity with slight stimulatory effects on prolactin, ACTH, and cortisol; their GH-releasing activities were directly compared for the first time.
Arvat, E; di Vito, L; Maccagno, B; Broglio, F; Boghen, M F; Deghenghi, R; Camanni, F; Ghigo, E · RCT
RPEP-00398 · 1997GHRP-2 stimulation revealed significant residual GH secretory potential in children classified as GH-deficient, with peak responses varying by growth disorder type.
Bercu, B B; Walker, R F · Clinical Trial
RPEP-00400 · 1997Oral MK-677 stimulated GH and IGF-I in selected severely GH-deficient adults, with responses dependent on residual pituitary secretory capacity.
Chapman, I M; Pescovitz, O H; Murphy, G; Treep, T; Cerchio, K A; Krupa, D; Gertz, B; Polvino, W J; Skiles, E H; Pezzoli, S S; Thorner, M O · RCT
RPEP-00401 · 1997GHRP-2 and GHRP-6 each synergize with GRF/GHRH but combining both GHRPs at maximal doses adds no further GH release, confirming shared receptor competition.
Cheng, J; Wu, T J; Butler, B; Cheng, K · In Vitro
RPEP-00402 · 1997Prolonged oral MK-677 significantly improved sleep quality by increasing stage 4 (deep sleep) and REM sleep in both young (18-30) and older (65+) adults.
Copinschi, G; Leproult, R; Van Onderbergen, A; Caufriez, A; Cole, K Y; Schilling, L M; Mendel, C M; De Lepeleire, I; Bolognese, J A; Van Cauter, E · RCT
RPEP-00404 · 1997Octreotide (somatostatin analog) attenuated GH secretagogue-induced Fos expression in the arcuate nucleus, showing somatostatin opposes GHRP action centrally.
Dickson, S L; Viltart, O; Bailey, A R; Leng, G · Animal Study
RPEP-00412 · 1997Anti-beta-endorphin antibodies blocked suckling-induced prolactin release without affecting tuberoinfundibular dopaminergic neurons, proving beta-endorphin is an essential mediator.
Jaworski, R P; Callahan, P; Janik, J · Animal Study
RPEP-00417 · 1997Hexarelin's GH-releasing effect is significantly modulated by somatostatin tone, with somatostatin withdrawal amplifying the GH response to hexarelin.
Massoud, A F; Hindmarsh, P C; Brook, C G · Clinical Trial
RPEP-00418 · 1997GH secretagogue receptors are molecularly confirmed in both pituitary and hypothalamus, using a distinct signal transduction pathway from GHRH.
McKee, K K; Palyha, O C; Feighner, S D; Hreniuk, D L; Tan, C P; Phillips, M S; Smith, R G; Van der Ploeg, L H; Howard, A D · In Vitro
RPEP-00422 · 1997Intranasal GHRP-2 effectively stimulated GH release in children with short stature, demonstrating viability of a needle-free delivery route.
Pihoker, C; Badger, T M; Reynolds, G A; Bowers, C Y · Clinical Trial
RPEP-00424 · 1997GH secretagogues activate hypothalamic neurons and require an intact GHRH system for full in vivo potency, despite being able to release GH directly from the pituitary.
Robinson, I C · Review
RPEP-00434 · 1997GHRH and GHRPs can restore GH secretion in aging and disease, addressing the visceral fat accumulation and metabolic changes associated with GH decline.
Thorner, M O; Chapman, I M; Gaylinn, B D; Pezzoli, S S; Hartman, M L · Review
RPEP-00436 · 1997Continuous GHRH plus GHRP-2 infusion partially restored GH pulsatility and substantially raised IGF-1 levels in critically ill patients with suppressed somatotropic axes.
Van den Berghe, G; de Zegher, F; Veldhuis, J D; Wouters, P; Awouters, M; Verbruggen, W; Schetz, M; Verwaest, C; Lauwers, P; Bouillon, R; Bowers, C Y · Clinical Trial
RPEP-00437 · 1997Prolonged critical illness disrupts spontaneous TSH and prolactin secretion, and GH secretagogue infusion affects these hormones alongside GH stimulation.
Van den Berghe, G; de Zegher, F; Veldhuis, J D; Wouters, P; Gouwy, S; Stockman, W; Weekers, F; Schetz, M; Lauwers, P; Bouillon, R; Bowers, C Y · Clinical Trial
RPEP-00443 · 1997SSTR2 knockout mice showed no growth hormone negative feedback on arcuate nucleus neurons, demonstrating that this receptor subtype is essential for GH autoregulation.
Zheng, H; Bailey, A; Jiang, M H; Honda, K; Chen, H Y; Trumbauer, M E; Van der Ploeg, L H; Schaeffer, J M; Leng, G; Smith, R G · Animal Study
RPEP-00448 · 1998Sequential backbone modifications of ipamorelin produced smaller peptidomimetic compounds that retained potent GH secretagogue activity, advancing the goal of orally active GH-releasing peptides.
Ankersen, M; Johansen, N L; Madsen, K; Hansen, B S; Raun, K; Nielsen, K K; Thogersen, H; Hansen, T K; Peschke, B; Lau, J; Lundt, B F; Andersen, P H · In Vitro