Induction of analgesia by central administration of ORG 2766, an analog of ACTH4-9

Dose-dependent analgesia was produced by microinjection of ORG 2766 into the periaqueductal gray (PAG). This analgesia was found to be potent and long-lasting and occurred at doses which were equimolar to those necessary for morphine analgesia. The same doses failed to produce analgesia by the cerebroventricular route, suggesting that the PAG was the site of action of this effect. Naloxone failed to reduce the analgesia and morphine tolerance did not diminish the effect significantly. Additionally, ORG 2766 at concentrations up to 10 [mu]M failed to inhibit binding of [3H]naloxone to brain opiate receptors in vitro. These results suggest a non-opiate mechanism of action and are discussed in terms of a proposed [alpha]-MSH or ACTH receptor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24482/1/0000757.pd

Brain Activation by Peptide Pro-Leu-Gly-NH2 (MIF-1)

MIF-1 (Pro-Leu-Gly-NH2) is a tripeptide for which the therapeutic potential in Parkinson's disease and depression has been indicated by many studies. However, the cellular mechanisms of action of MIF-1 are not yet clear. Here, we show the specific brain regions responsive to MIF-1 treatment by c-Fos mapping, and determine the kinetics of cellular signaling by western blotting of pERK, pSTAT3, and c-Fos in cultured neurons. The immunoreactivity of c-Fos was increased 4 hours after MIF-1 treatment in brain regions critically involved in the regulation of mood, anxiety, depression, and memory. The number of cells activated was greater after peripheral treatment (intravenous delivery) than after intracerebroventricular injection. In cultured SH-SY5Y neuronal cells, c-Fos was induced time- and dose-dependently. The activation of cellular c-Fos was preceded by a transient increase of mitogen-activated protein kinase pERK but a reduction of phosphorylated Signal Transducer and Activator of Transcription (pSTAT3) initially. We conclude that MIF-1 can modulate multiple cellular signals including pERK, and pSTAT3 to activate c-Fos. The cellular activation in specific brain regions illustrates the biochemical and neuroanatomical basis underlying the therapeutic effect of MIF-1 in Parkinson's disease and depression

Handbook of biologically active peptides /

"Peptides play a crucial role in many physiological processes including actions as neurotransmitters, hormones, and antibiotics. Research has shown their importance in such fields as neuroscience, immunology, pharmacology, and cell biology. The Handbook of Biologically Active Peptides presents, for the first time, this tremendous body of knowledge in the field of biologically active peptides in one single reference. The section editors and contributors represent some of the most sophisticated and distinguished scientists working in basic sciences and clinical medicine. The Handbook of Biologically Active Peptides is a definitive, all-encompassing reference that will be indispensable for individuals ranging from peptide researchers, to biochemists, cell and molecular biologists, neuroscientists, pharmacologists, and to endocrinologists. Chapters are designed to be a source for workers in the field and will enable researchers working in a specific area to examine other related areas with which they would not ordinarily be familiar"--Publisher's description.Online resource; title from digital title page (ebrary, viewed on July 11, 2014)."Peptides play a crucial role in many physiological processes including actions as neurotransmitters, hormones, and antibiotics. Research has shown their importance in such fields as neuroscience, immunology, pharmacology, and cell biology. The Handbook of Biologically Active Peptides presents, for the first time, this tremendous body of knowledge in the field of biologically active peptides in one single reference. The section editors and contributors represent some of the most sophisticated and distinguished scientists working in basic sciences and clinical medicine. The Handbook of Biologically Active Peptides is a definitive, all-encompassing reference that will be indispensable for individuals ranging from peptide researchers, to biochemists, cell and molecular biologists, neuroscientists, pharmacologists, and to endocrinologists. Chapters are designed to be a source for workers in the field and will enable researchers working in a specific area to examine other related areas with which they would not ordinarily be familiar"--Publisher's description.Includes bibliographical references and index.Plant peptides / Yoshikatsu Matsubayashi -- Bacterial/antibiotic peptides / Robert E.W. Hancock -- Fungal peptides / Tzi Bun Ng -- Invertebrate peptides / Ronald J. Nachman -- Amphibian/skin peptides / J. Michael Conlon -- Venom peptides / Jean-Marc Sabatier -- Cancer/anticancer peptides / Terry Moody -- Vaccine peptides / Pravin T.P. Kaumaya -- Immune/inflammatory peptides / Joost Oppenheim -- Brain peptides / Hubert Vaudry -- Edocrine peptides / Ludwik Malendowicz -- Ingestive peptides / Stephen C. Woods -- Gastrointestinal peptides / Yvette Taché -- Cardiovascular peptides / Kazuhiro Takahashi -- Renal peptides / Willis K. Samson -- Respiratory peptides / Sami Said -- Opiate peptides / Fred Nyberg -- Neurotrophic peptides / Illana Gozes -- Blood-brain peptides / Weihong Pan -- Peptide biosynthesis/processing / Naoto Minamino -- section XXI. General peptide topics / Abba J. Kastin.Elsevie

Orexin A but Not Orexin B Rapidly Enters Brain from Blood by Simple Diffusion 1

ABSTRACT We determined the ability of orexin A and orexin B, recently discovered endogenous appetite enhancers, to cross the blood-brain barrier (BBB) of mice. Multiple time-regression analysis showed that an i.v. bolus of 125 I-orexin A rapidly entered the brain from the blood, with an influx rate (K i ϭ 2.5 Ϯ 0.3 ϫ 10 Ϫ4 ml/g⅐min) many times faster than that of the 99m Tcalbumin control. This relatively rapid rate of entry was not reduced by administration of excess orexin A (or leptin) or by fasting for 22 h, even when penetration into only the hypothalamus was measured. Lack of saturability also was shown by perfusion in blood-free buffer. HPLC revealed that most of the injected 125 I-orexin A reached the brain as intact peptide. Capillary depletion studies showed that the administered peptide did not remain bound to the endothelial cells comprising the BBB but reached the brain parenchyma. Efflux of 125 I-orexin A from the brain occurred at the same rate as 99m Tc-albumin. The octanol/buffer partition coefficient of 0.232 showed that orexin A was highly lipophilic, whereas the value for orexin B was only 0.030. Orexin B, moreover, was rapidly degraded in blood, so no 125 I-orexin B could be detected in intact form in brain when injected peripherally. Thus, although orexin B is rapidly metabolized in blood and has low lipophilicity, orexin A rapidly crosses the BBB from blood to reach brain tissue by the process of simple diffusion. The orexins were named for the Greek word for appetite The orexins were discovered during a search for peptides that activate orphan receptors whose amino acid sequences show the structural hallmarks of cell surface receptors for G proteins To assess the therapeutic potential of the orexins for the treatment of anorexia, it would be helpful to know their ability to cross the blood-brain barrier (BBB) from the periphery. Accordingly, the rate of entry into brain of i.v. 125 Ilabeled orexin A and orexin B was quantified by multiple time-regression analysis. HPLC was used to determine whether the 125 I-orexins penetrated the BBB in intact form. Capillary depletion was used to determine whether most of the 125 I-orexin reaching the brain was in the parenchyma or was bound to the endothelial cells comprising the BBB. 99m Tc-labeled albumin was injected together with the 125 Iorexin to reflect the vascular space and any disruption of the BBB. The octanol-to-buffer ratio was used to measure the lipophilicity of the orexins. Efflux from the brain and entry by a blood-free i.v. perfusion also were tested. Materials and Methods Multiple Time-Regression Analysis of Entry into Brain. Adult male albino ICR mice (Charles River, Wilmington, MA) (10 per group and weighing about 22 g) were anesthetized with urethane (4 g/kg i.p.). Orexin was radiolabeled with 125 I by the chloramine-T method and purified on a column of Sephadex G-10. Acid precipitation showed incorporation of 125 I into orexin of 95.7% to 99.6% for the iodinations used in this study. HPLC of the 125 I-orexin immediately before use showed more than 90% purity each time. The specific activity of 125 I-orexin A was 126 Ci/mmol, and that o

Leptin: A biomarker for sleep disorders?

Photograph of the exterior of the Frank Phillips Home

Autoregulation of Release of Melanocyte Stimulating Hormone from the Rat Pituitary

MELANOCYTE stimulating hormone (MSH) enables amphibians such as the frog to change skin colour and thereby adapt to the environment. The function of this pituitary hormone in mammals such as the albino rat has not been established

Tyr-MIF-1 Attenuates Development of Tolerance to Spiperone-Induced Catalepsy in Rats

Because the tripeptide MIF-1 (Pro-Leu-Gly-NH2) is known to attenuate the effects of neuroleptic-induced catalepsy as well as neuroleptic-induced proliferation of dopamine (DA) receptors, we studied the related naturally occurring peptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) for similar properties. Male rats were treated SC for 11 consecutive days with either the DA D1 receptor antagonist SCH 23390 HC1 (0.50 mg/kg per day), the DA D2 receptor antagonist spiperone HCl (0.30 mg/kg per day), or vehicle. Half the rats were cotreated daily with Tyr-MIF-1 (1.0 mg/kg per day). The cataleptic effects of SCH 23390 were not altered by Tyr-MIF-1. Tolerance to SCH 23390-induced catalepsy did not develop during the 11-day treatment, and Tyr-MIF-1 had no effect on SCH 23390-induced catalepsy. However, tolerance developed to spiperone-induced catalepsy, and Tyr-MIF-1 attenuated this development of tolerance (p \u3c 0.001). Locomotor and stereotyped activities of the DA D1 and D2 agonists, SKF 39393 (3.0 mg/kg) and quinpirole (3.0 mg/kg) were not affected by Tyr-MIF-1 after treatment with the DA antagonists was discontinued. Tyr-MIF-1 did not alter the Bmax or Kd for in vitro binding of [3H]SCH 23390 and [3H]spiperone to homogenates of the striatum. These findings indicate that Tyr-MIF-1 is able to selectively affect the development of receptor tolerance to a DA D2 receptor antagonist, and that this effect is unrelated to changes in affinity or numbers of D2 receptors

MSH activity in pituitaries of rats treated with hypothalamic extracts

Melanocyte-stimulating hormone (MSH) activity of pituitaries from rats receiving hypothalamic extracts was increased as compared with controls. The hypothalamic extracts also lightened frogs previously darkened by removal of the hypothalamic region. These results further support the concept of the existence of a hypothalamic factor which inhibits the release of MSH from the pituitary