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RPEP-00037 · 1986

Thymosin Fraction 5 Boosted Immune Cell Receptor Expression in Human Cells

Thymosin fraction 5 (TF5), a mix of thymic peptides, significantly increased both the percentage of human lymphocytes expressing IL-2 receptors (IL-2R) and the density of receptors on each cell. This happened after the cells were stimulated with PHA (a plant protein that activates immune cells). Synthetic thymosin alpha 1 alone produced the same effect, identifying it as the active ingredient in TF5. The effect was direct. When researchers used cyclosporin A (a drug that blocks IL-2 production), TF5 still increased IL-2R expression. This means thymosin works by directly putting more receptors on cells, not by making more IL-2. More receptors led to stronger cell multiplication.

Sztein, M B; Serrate, S A; Goldstein, A L · In Vitro

RPEP-00043 · 1987

Interleukin-2: The Immune Growth Factor That Fights Cancer

IL-2 is a 133-amino acid protein (molecular weight 15,420 daltons) produced by activated T-cells. Its gene sits on chromosome 4. The IL-2 receptor is a 272-amino acid protein (55,000 daltons). IL-2 does not just make immune cells copy themselves. It moves cells from a resting state (G1) through to DNA synthesis (S phase). During this process, the proto-oncogene c-myb increases 6 to 7 times above normal levels. The most exciting clinical development: IL-2 could expand LAK cells (lymphokine-activated killer cells) and TIL (tumor-infiltrating lymphocytes) that attack cancer. Early human trials showed both therapeutic promise and significant toxicity. Thymosin fraction 5 and thymosin alpha 1 could modulate IL-2 receptor expression on human blood cells, potentially increasing the effectiveness of IL-2 therapy.

Fletcher, M; Goldstein, A L · Review

RPEP-00046 · 1987

Different Opioid Peptides Raise Stress Hormones Through Different Receptors

All 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 · 1987

Time of Day Matters: Opioid Peptides Trigger Different Hormone Responses Morning vs. Afternoon

Beta-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-00053 · 1987

Repeated Brain Stimulation for Pain Relief Led to Tolerance That Could Be Overcome

Electrical stimulation of the periaqueductal grey (PAG, a brain region that controls pain) initially produced strong pain relief in rats. With repeated stimulation, this relief gradually disappeared. The tolerance was not from opioid depletion. Brain levels of beta-endorphin, met-enkephalin, and dynorphin were unchanged in tolerant rats compared to controls. It was not a learned (conditioned) response either. Tolerant rats exposed to all the cues associated with stimulation showed no compensatory pain increase. And repeated exposure to the cues without stimulation did not restore pain relief. The tolerance behaved exactly like drug tolerance: the dose-response curve shifted right (needed more stimulation for the same effect), it was reversed by naloxone, and it recovered spontaneously over time. Tolerant rats also showed cross-tolerance to morphine, confirming the same opioid receptor system was involved. Rats showed no signs of stress during the protocol: normal body weight, food intake, temperature, adrenal weight, and hormone levels.

Millan, M J; Członkowski, A; Herz, A · Animal Study

RPEP-00070 · 1988

How Opioid Peptides Control Blood Pressure Through the Hypothalamus

The three families of opioid peptides (dynorphins, endorphins, and enkephalins) all have cardiovascular effects. Dynorphins prefer kappa receptors, enkephalins prefer delta and mu receptors, and beta-endorphin prefers mu and delta receptors. The review focused on mu-opioid receptors in the hypothalamus, a brain region that controls many body functions including blood pressure. While the opioid system's role in normal blood pressure regulation was not well understood, cardiovascular stress clearly activates the opioid system. The review covered both normal cardiovascular regulation and pathological states like hypertension, hemorrhagic shock, and heart failure, where opioid system changes had been documented.

Feuerstein, G; Sirén, A L · Review

RPEP-00071 · 1988

Mu-Opioid Receptors in the Brain Reduce Stomach Acid More Than Gut Receptors

Morphine and other mu-opioid agonists decreased gastric acid secretion. They were more potent when injected into the brain (i.c.v.) than into the blood (i.v.), indicating a central mechanism. The quaternary opioid antagonist naltrexone methylbromide (which cannot cross the blood-brain barrier) blocked brain-injected morphine's effect and partially blocked IV morphine's effect. This confirmed morphine reduces acid through brain receptors, even when given intravenously. The kappa-selective agonist U-50,488H had the opposite effect: it increased gastric acid when given IV but not when given into the brain. This increase was blocked by naloxone, the muscarinic blocker atropine, and the M1-selective blocker pirenzepine. The delta-selective agonist DPDPE did not affect acid secretion by either route.

Fox, D A; Burks, T F · Animal Study

RPEP-00073 · 1988

Opioid Peptides Relaxed Blood Vessels by Blocking Nerve Signals

In rabbit ear and saphenous (leg) arteries, both delta-selective opioid agonists (leu-enkephalin and met-enkephalin) and kappa-selective agonists (dynorphin-(1-13) and ethylketocyclazocine) inhibited nerve-stimulation-evoked contractions. Delta agonists showed a vessel-specific difference: their maximum inhibitory effect was significantly less in the saphenous artery than in the ear artery. Kappa agonists worked similarly in both vessels. Yohimbine (an alpha-2 adrenergic blocker) did not enhance opioid inhibitory effects at any stimulation frequency in either vessel. This disproved the hypothesis that opioid receptors work by boosting alpha-2 receptor inhibition of noradrenaline release.

Gan, E A; Duckles, S P · In Vitro

RPEP-00074 · 1988

Mu-Opioid Receptors in the Amygdala Control Feeding Behavior

The mu-selective opioid agonist DAGO (Tyr-D-Ala-Gly-(Me)Phe-Gly-ol) increased food intake when injected into the central nucleus of the amygdala at doses of 1 and 3 nanomoles. Neither DSLET (a delta-selective agonist) nor dynorphin A (a kappa-selective agonist) affected food intake at the same location, even at the highest dose of 3 nanomoles. Dynorphin A did increase food intake when injected into the medial hypothalamus at 2 nanomoles. This shows that different brain regions use different opioid receptor types to control eating. Bilateral injections of DAGO were no more effective than unilateral injections. Naloxone and the long-acting antagonist beta-chlornaltrexamine both blocked DAGO's feeding effect, confirming opioid receptor involvement.

Gosnell, B A · Animal Study

RPEP-00077 · 1988

Cortisol Blocked Opioid-Induced Prolactin Release in Rats

Cortisol 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-00079 · 1988

How the Hypothalamus Uses Peptide Receptors to Control Hormones

Endogenous opioid peptides inhibit the release of both vasopressin and oxytocin from the posterior pituitary. They also affect anterior pituitary hormones through the hypothalamic portal blood system. Dynorphin mRNA co-exists in the same neurons as vasopressin. Stimuli that increase vasopressin secretion (like salt loading) also increase dynorphin mRNA accumulation. This parallel regulation strongly suggests dynorphin has a genuine role alongside vasopressin. Pro-enkephalin A mRNA co-exists with CRF in a different group of hypothalamic cells. Stresses that increase CRF mRNA also increase pro-enkephalin mRNA in the same area. The co-existence of opioid peptides with established hormones in the same cells, combined with their coordinated regulation, provides powerful evidence that opioids are genuine neuroendocrine regulators, not incidental bystanders.

Lightman, S L · Review

RPEP-00085 · 1988

Delta-Opioid Peptide Triggered Hibernation in Active Ground Squirrels

DADLE (D-Ala2-D-Leu5 enkephalin), a delta-opioid receptor agonist, at 1.50 mg/kg/day induced summer hibernation comparable to that caused by natural Hibernation Induction Trigger (HIT). Morphine (1.50 mg/kg/day), morphiceptin (0.82 mg/kg/day), and dynorphin A (0.82 mg/kg/day) did not induce hibernation. Strikingly, morphine, morphiceptin, and dynorphin A actually antagonized HIT-induced hibernation. They blocked the natural hibernation signal. This suggests delta-opioid receptors promote hibernation while mu and kappa opioid receptors promote the arousal (waking) state. Natural hibernation may involve a shift in the balance between these receptor systems.

Oeltgen, P R; Nilekani, S P; Nuchols, P A; Spurrier, W A; Su, T P · Animal Study

RPEP-00086 · 1988

Naloxone Enhanced Delayed Stomach Contractions Triggered by Vagus Nerve

Naloxone (100 to 1000 micrograms/kg) did not affect the initial stomach response to vagus nerve stimulation. But it dose-dependently enhanced the delayed response (from vagal afferent fibers). This means endogenous opioids normally restrain the delayed stomach excitation. Met-enkephalin was markedly more potent than the mu-agonist DAGO and the kappa-agonist dynorphin A(1-13) at inhibiting both types of vagal stomach responses. The delta-selective agonist DPDPE mimicked met-enkephalin's inhibitory effects. The delta-selective antagonist ICI 174,864 blocked DPDPE's effects. This confirmed delta-opioid receptors mediate the gastric inhibition. The conclusion: natural opioid peptides (likely enkephalins) tonically restrain vagus nerve-driven stomach excitation through delta receptors.

Okamoto, T; Kurahashi, K; Fujiwara, M · Animal Study

RPEP-00089 · 1988

Two Mouse Strains Had Opposite Stress Pain Relief Despite Similar Opioid Systems

DBA mice had higher baseline pain thresholds than C57 mice. But C57 mice showed much greater stress-induced analgesia (pain relief from stress). The opioid systems differed genetically: DBA mice had significantly more dynorphin in the hypothalamus and neurointermediate pituitary. C57 mice had lower KD values (better affinity) for spinal mu receptors but higher KD (lower affinity) for cerebral kappa receptors. Under stress, the two strains activated different opioid systems. C57 mice: beta-endorphin decreased in hypothalamus and increased in neurointermediate pituitary lobe. DBA mice: dynorphin decreased in hypothalamus and beta-endorphin increased in the anterior pituitary. Both strains showed spinal cord dynorphin decreases under stress.

Przewłocka, B; Vetulani, J; Lasoń, W; Dziedzicka, M; Silberring, J; Castellano, C; Przewłocki, R · Animal Study

RPEP-00091 · 1988

Beta-Endorphin Specifically Binds to Lung and Liver in Living Rats

Radioactive beta-endorphin injected intravenously accumulated specifically in the lung and liver but not other tissues. Four lines of evidence confirmed this was specific receptor binding, not passive trapping. First, adding excess unlabeled beta-endorphin reduced the labeled peptide in lung and liver. Second, injecting unlabeled beta-endorphin via the femoral vein (which passes through the lungs first) rapidly increased blood levels of the pre-injected labeled peptide, displacing it from lung binding sites. Injection via the carotid artery (bypassing the lungs) did not have this effect. Third, immunoreactive labeled peptide that had lost its receptor-binding ability did not accumulate in lung or liver. Fourth, dynorphin (1-13) and ethylketocyclazocine (kappa agonist) displaced beta-endorphin from these sites, but DADLE (delta agonist) and naloxone (mu antagonist) did not. This pharmacological profile indicates kappa-type binding sites.

Sato, H; Sugiyama, Y; Sawada, Y; Iga, T; Hanano, M · Animal Study

RPEP-00092 · 1988

Gallbladder Muscle Cells Contracted in Response to Opioid Peptides

Three opioid peptides caused dose-dependent contraction of isolated gallbladder muscle cells: met-enkephalin > dynorphin(1-13) > leu-enkephalin. The contractions were blocked by the opioid antagonists naloxone and MR2266 but not by muscarinic, CCK/gastrin, or tachykinin antagonists. This confirmed the response was specifically through opioid receptors. Differential sensitivity to preferential antagonists of mu (naloxone) and kappa (MR2266) receptors, combined with the different potencies of the three agonists, indicated the presence of mu, delta, and kappa opioid receptors on the gallbladder muscle cells. These opioid peptides are known to be present in myenteric neurons of the gut, providing the natural source of opioid signals for gallbladder muscle.

Severi, C; Grider, J R; Makhlouf, G M · In Vitro

RPEP-00094 · 1988

Different Opioid Peptides Had Opposite Effects on Brain Reward in Different Regions

Leu-enkephalin and leu-enkephalinamide inhibited electrical self-stimulation in the substantia nigra/ventral tegmental area (SN-VTA) but not the medial forebrain bundle/lateral hypothalamus (MFB-LH). However, injection into MFB-LH facilitated self-stimulation of the distant SN-VTA. Ala-leu-enkephalin injected into SN-VTA actually facilitated its self-stimulation (opposite to leu-enkephalin). The same peptide in MFB-LH facilitated SN-VTA stimulation like the other enkephalins. Dynorphin A(1-13) injected into SN-VTA facilitated its self-stimulation. Injection into MFB-LH had no effect. Met-enkephalin had no direct or indirect effects in either region. These differences likely reflect different receptor preferences in the SN-VTA neural organization.

Singh, J; Desiraju, T · Animal Study