Presence of Substance P Positive Terminals on Hypothalamic
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Vasopressin Release from the Rat Hypothalamo-Neurohypophysial System: Effects of Tachykinin NK–1 and NK–2 Receptors Agonis
Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu Vasopressin release from the rat hypothalamo-neurohy- pophysial system: Effects of tachykinin NK–1 and NK–2 receptors agonists and antagonists ARTICLE ORIGINAL Marlena Juszczak Department of Pathophysiology, Medical University of Lodz, Lodz, Poland. Correspondence to: Marlena Juszczak, Ph.D., D.Sc. Department of Pathophysiology Medical University of Lodz Narutowicza 60 90-136 Lodz, POLAND TEL/FAX: +48 42 6306187 [email protected] Submitted: July 7, 2004 Accepted: October 15, 2004 Key words: tachykinin receptors; substance P; neurokinin A; vasopressin Neuroendocrinol Lett 2005; 26(4):367–372 PMID: 16136007 NEL260405A13 © Neuroendocrinology Letters www.nel.edu Abstract OBJECTIVES: Present experiments were undertaken to study the influence of pep- tide NK–1 and NK–2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on vasopres- sin (AVP) secretion from the rat hypothalamo-neurohypophysial (HN) system in vitro. RESULTS: The results showed that both substance P and highly selective tachykinin 9 11 NK–1 receptor agonist, i.e., [Sar ,Met(O2) ]-Substance P, enhanced significantly AVP secretion, while the NK–1 receptor antagonist (Tyr6,D–Phe7,D–His9)-Sub- stance P (6–11) – sendide – was found to antagonize the substance P–induced hormone release from isolated rat HN system (all peptides at the concentration of 10–7 M/L). The NK–2 receptor selective agonist (β–Ala8)–Neurokinin A (4–10) was essentially inactive in modifying AVP release from the rat HN system in vitro, while neurokinin A (the natural ligand for this tachykinin receptor) was found to stimulate the AVP release; this effect of neurokinin A has been diminished by the 5 6,8,9 10 NK–2 receptor antagonist (Tyr ,D–Trp ,Lys–NH2 )–Neurokinin A (4–10). -
Europium-Labeled Ligands for Receptor Binding Studies
Europium-labeled Ligands for Receptor Binding Studies Katja Sippola, Maija-Liisa Mäkinen, Sanna Rönnmark, Joni Helenius, Riitta Heilimö, Anu Koivikko, Pertti Hurskainen and Christel Gripenberg-Lerche PerkinElmer Life and Analytical Sciences, Wallac Oy 1 Introduction 2 Methods Time-resolved fluorescence enhancement technique DELFIA® enables development of highly sensitive assays for screening. We have developed a family of Europium-labeled peptides and proteins designed for ligand receptor binding assays that can be easily automated The DELFIA® ligand receptor binding assay is based on dissociation-enhanced time-resolved fluorescence. DELFIA® Eu-labeled ligand and and optimized either for 96 or 384 well format. These Eu-labeled ligands provide an excellent non-radioactive alternative that is both receptor membrane preparate are incubated on an filter plate (PALL AcroWell or AcroPrep) after which unbound labeled ligand is removed by stabile and sensitive. filtration. Eu is dissociated from the bound ligand by using DELFIA® Enhancement Solution. Dissociated Eu creates highly fluorescent complexes, ® The new tachycinin members of the DELFIA ligand family are Substance P and Neurokinin A. These peptide ligands have many which are measured in a multilabel counter with TRF option, e.g. EnVision™. physiological roles, e.g. they stimulate smooth muscle contraction and glandular secretion and are involved in immune responses and neurotransmission. 3 DELFIA® Neurokinin A assays on 96 well filtration plates 4 DELFIA® Substance P assays on 96 well -
Role of Tachykinin Receptors and Melatonin in Oxytocin
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2004, 55, 4, 739749 www.jpp.krakow.pl M. JUSZCZAK, K. FURYKIEWICZ-NYKI, B. STEMPNIAK ROLE OF TACHYKININ RECEPTORS AND MELATONIN IN OXYTOCIN SECRETION FROM ISOLATED RAT HYPOTHALMO- NEUROHYPOPHYSIAL SYSTEM Department of Pathophysiology, Medical University of £ód, £ód, Poland Present investigations were undertaken to study the influence of peptide NK-1 and NK-2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on oxytocin (OT) release from isolated rat hypothalamo-neurohypophysial (H-N) system as well as to determine whether the tachykinin NK-1 and/or NK-2 receptors contribute to the response of oxytocinergic neurons to melatonin. The results show, for the first time, that highly selective NK- 9 11 1 receptor agonist, i.e., [Sar ,Met(O2) ]-Substance P, enhances while the NK-1 6 7 9 receptor antagonist (Tyr ,D-Phe ,D-His )-Substance P (6-11) - sendide - diminishes significantly OT secretion; the latter peptide was also found to antagonize the substance P-induced hormone release from isolated rat H-N system, when used at the -7 concentration of 10 M/L. Melatonin significantly inhibited basal and substance P- stimulated OT secretion. Neurokinin A and the NK-2 receptor selective agonist (ß- 8 5 6,8,9 Ala )-Neurokinin A (4-10) as well as the NK-2 receptor antagonist (Tyr ,D-Trp , 10 Lys-NH2 )-Neurokinin A (4-10) were essentially inactive in modifying OT release from the rat H-N system in vitro. The present data indicate a distinct role for tachykinin NK-1 (rather than NK-2) receptor in tachykinin-mediated regulation of OT secretion from the rat H-N system. -
Substance P and Antagonists of the Neurokinin-1 Receptor In
Martinez AN and Philipp MT, J Neurol Neuromed (2016) 1(2): 29-36 Neuromedicine www.jneurology.com www.jneurology.com Journal of Neurology & Neuromedicine Mini Review Article Open Access Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System Alejandra N. Martinez1 and Mario T. Philipp1,2* 1Division of Bacteriology & Parasitology, Tulane National Primate Research Center, Covington, LA, USA 2Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA Article Info ABSTRACT Article Notes This review addresses the role that substance P (SP) and its preferred receptor Received: May 03, 2016 neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, Accepted: May 18, 2016 viral, parasitic, and neurodegenerative diseases of the central nervous system. *Correspondence: The SP/NK1R complex is a key player in the interaction between the immune Division of Bacteriology and Parasitology and nervous systems. A common effect of this interaction is inflammation. For Tulane National Primate Research Center this reason and because of the predominance in the human brain of the NK1R, Covington, LA, USA its antagonists are attractive potential therapeutic agents. Preventing the Email: [email protected] deleterious effects of SP through the use of NK1R antagonists has been shown © 2016 Philipp MT. This article is distributed under the terms of to be a promising therapeutic strategy, as these antagonists are selective, the Creative Commons Attribution 4.0 International License potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to Keywords clinical management of CNS inflammation. -
Distribution of Neurokinin 2 and 3 Receptor Mrna in the Normal
Distribution of Neurokinin 2 and 3 Receptor mRNA in the Normal Equine Gastrointestinal Tract and Effect of Inflammation on Expression of Neurokinin 1, 2 and 3 Receptor mRNA in the Jejunum by Dr. Christina Martin A Thesis presented to The University of Guelph In partial fulfillment of requirements for the degree of Masters of Science in Clinical Studies Guelph, Ontario, Canada Dr. Christina Martin, April, 2014 ABSTRACT DISTRIBUTION OF NEUROKININ 2 AND 3 RECEPTOR mRNA IN THE NORMAL EQUINE GASTROINTESTINAL TRACT AND EFFECT OF INFLAMMATION ON EXPRESSION OF NEUROKININ 1, 2 AND 3 RECEPTOR mRNA IN THE JEJUNUM Dr. Christina E. W. Martin Advisor: University of Guelph, 2014 Dr. Judith B. Koenig This study is an investigation of the distribution of neurokinin receptors in the equine gastrointestinal tract. The objectives of this research were to determine the relative distribution of neurokinin 2 (NK2) and 3 (NK3) receptor mRNA in the normal equine gastrointestinal tract, and also to determine changes in neurokinin 1 (NK1), NK2 and NK3 receptor mRNA expression after ischemia/reperfusion injury or intraluminal distension in the jejunum. Samples from 9 regions in the gastrointestinal tract (duodenum, jejunum, ileum, caecum, right ventral colon, left ventral colon, pelvic flexure, right dorsal colon and left dorsal colon) were harvested from 5 mature healthy horses, euthanized for reasons unrelated to the gastrointestinal tract, for the study of NK2 and NK3 mRNA distribution in the normal intestinal tract. To evaluate the effect of inflammation on NK1, NK2 and NK3 receptor mRNA distribution, samples were taken from 6 horses whose jejunum underwent one of three treatments: control (sham-operated), intraluminal distension (ILD) or ischemic strangulation obstruction and subsequent reperfusion injury (ISO). -
The Significance of NK1 Receptor Ligands and Their Application In
pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59). -
Tachykinins in Endocrine Tumors and the Carcinoid Syndrome
European Journal of Endocrinology (2008) 159 275–282 ISSN 0804-4643 CLINICAL STUDY Tachykinins in endocrine tumors and the carcinoid syndrome Janet L Cunningham1, Eva T Janson1, Smriti Agarwal1, Lars Grimelius2 and Mats Stridsberg1 Departments of 1Medical Sciences and 2Genetics and Pathology, University Hospital, SE 751 85 Uppsala, Sweden (Correspondence should be addressed to J Cunningham who is now at Section of Endocrine Oncology, Department of Medical Sciences, Lab 14, Research Department 2, Uppsala University Hospital, Uppsala University, SE 751 85 Uppsala, Sweden; Email: [email protected]) Abstract Objective: A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). Method: TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. Results: All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin- producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. -
Calcitonin Gene-Related Peptide and Other Peptides
P1: KWW/KKL P2: KWW/HCN QC: KWW/FLX T1: KWW GRBT050-16 Olesen- 2057G GRBT050-Olesen-v6.cls July 9, 2005 4:30 ••Chapter 16 ◗ Calcitonin Gene-Related Peptide and Other Peptides Susan Brain and Lars Edvinsson Vasoactive peptides can be either stored or synthesized de THE CGRP FAMILY OF PEPTIDES novo before release from a range of tissues in the brain or from the walls of intracranial vasculature. In this chapter, The expression of mRNA from the calcitonin gene is tissue we concentrate on neuropeptides that are released from specific in that CGRP mRNA is predominantly expressed perivascular nerves. These include calcitonin gene-related in nerves and calcitonin mRNA in the thyroid (5). The 37 peptide (CGRP), substance P, neurokinin A, nociceptin, amino acid peptide CGRP belongs to a family that include somatostatin, and opioids (Table 16-1). The endothelium the more recently discovered peptides adrenomedullin produces the potent vasoconstrictors endothelin and an- that is primarily produced by non-neuronal tissues, espe- giotensin, and dilators such as nitric oxide, prostacyclin, cially vascular tissues and amylin that is mainly produced and endothelium-derived hyperpolarizing factors. In ad- in the pancreas. They share some structural homology (ap- dition there are circulating agents; among these the most proximately 25–40%) and also some, but not total, similar- potent is 5-hydroxytryptamine. The neuronal messengers ities in biological activities (see Brain and Grant [11] for stored in the intracranial vessels have been reviewed recent review). CGRP is abundant in the body and has a (32) and it was revealed that sympathetic nerves store wide distribution throughout the central and peripheral noradrenaline, neuropeptide Y, and ATP, the parasympa- nervous systems. -
Calcitonin Gene-Related Peptide Regulates Expression of Neurokinin1 Receptors by Rat Spinal Neurons
1816 • The Journal of Neuroscience, March 1, 2003 • 23(5):1816–1824 Calcitonin Gene-Related Peptide Regulates Expression of Neurokinin1 Receptors by Rat Spinal Neurons Virginia S. Seybold,1 Kenneth E. McCarson,2 Paul G. Mermelstein,1 Rachel D. Groth,1 and Lia G. Abrahams1 1Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and 2Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 Although neurokinin 1 (NK1) receptors contribute to hyperalgesia, and their expression is increased in the spinal cord during peripheral inflammation, little is known regarding the signaling molecules and the second messenger pathways that they activate in regulating the expression of the NK1 receptor gene. Because the promoter region of the NK1 receptor contains a cAMP response element (CRE), we tested the hypothesis that calcitonin gene-related peptide (CGRP) regulates the expression of NK1 receptors via a pathway involving activation of the transcription factor cAMP response element binding protein (CREB). Experiments were conducted on primary cultures of neonatal rat spinal neurons. Treatment of cultures with CGRP for 8–24 hr increased 125I-substance P binding on spinal neurons; the increase in binding was preceded by an elevation in NK1 receptor mRNA. The CGRP-induced change in 125I-substance P binding was concentration-dependent and was inhibited by the antagonist CGRP8–37. CGRP increased phosphorylated CREB immunoreactivity and CRE-dependent transcription in neurons, indicating the involvement of the transcription factor CREB. Evidence that CGRP increased cAMP levels in spinal neurons and that the protein kinase A inhibitor H89 attenuated CGRP-induced CRE-dependent transcription suggests that the intracellular pathway stimulated by CGRP leads to activation of protein kinase A. -
The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 198 The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain ANNA JONSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9206-9 UPPSALA urn:nbn:se:uu:diva-241637 2015 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Friday, 8 May 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor of Medicine James Zadina (Tulane University School of Medicine, New Orleans, USA). Abstract Jonsson, A. 2015. The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 198. 64 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9206-9. There is an unmet medical need for the efficient treatment of neuropathic pain, a condition that affects approximately 10% of the population worldwide. Current therapies need to be improved due to the associated side effects and lack of response in many patients. Moreover, neuropathic pain causes great suffering to patients and puts an economical burden on society. The work presented in this thesis addresses SP1-7, (Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), a major metabolite of the pronociceptive neuropeptide Substance P (SP). SP is released in the spinal cord following a noxious stimulus and binds to the NK1 receptor. In contrast to SP, the degradation fragment SP1-7 is antinociceptive through binding to specific binding sites distinct from the NK1 receptor. -
Interaction Between Substance P and TRH in the Control of Prolactin Release
373 Interaction between substance P and TRH in the control of prolactin release B H Duvilanski, D Pisera, A Seilicovich, M del Carmen Díaz, M Lasaga, E Isovich and M O Velardez Centro de Investigaciones en Reproducción, Facultad de Medicina, Universidad de Buenos Aires, Argentina (Requests for offprints should be addressed to B H Duvilanski, Centro de Investigaciones en Reproducción, Facultad de Medicina, Piso 10, Universidad de Buenos Aires, Paraguay 2155 (1121) Buenos Aires, Argentina; Email: [email protected]) Abstract Substance P (SP) may participate as a paracrine and/or release. In order to study the interaction between TRH autocrine factor in the regulation of anterior pituitary and SP on prolactin release, anterior pituitaries were function. This project studied the effect of TRH on SP incubated with either TRH (107 M) or SP, or with both content and release from anterior pituitary and the role of peptides. SP (107 and 106 M) by itself stimulated SP in TRH-induced prolactin release. TRH (107 M), prolactin release. While 107 M SP did not modify the but not vasoactive intestinal polypeptide (VIP), increased TRH effect, 106 M SP reduced TRH-stimulated pro- immunoreactive-SP (ir-SP) content and release from male lactin release. SP (105 M) alone failed to stimulate rat anterior pituitary in vitro. An anti-prolactin serum also prolactin release and markedly decreased TRH-induced increased ir-SP release and content. In order to determine prolactin release. The present study shows that TRH whether intrapituitary SP participates in TRH-induced stimulates ir-SP release and increases ir-SP content in the prolactin release, anterior pituitaries were incubated with anterior pituitary. -
Neurokinin Regulation of Midbrain Raphe Neurons: a Behavioral and Anatomical Study
Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 1988 Neurokinin Regulation of Midbrain Raphe Neurons: A Behavioral and Anatomical Study Joseph Paris Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Medical Pharmacology Commons Recommended Citation Paris, Joseph, "Neurokinin Regulation of Midbrain Raphe Neurons: A Behavioral and Anatomical Study" (1988). Dissertations. 2519. https://ecommons.luc.edu/luc_diss/2519 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 1988 Joseph Paris NEUROKININ REGUI.ATION OF MIDBRAIN RAPHE NEURONS: A BEHAVIORAL AND ANATOMICAL STUDY by Joseph M. Paris A Dissertation Submitted to the Faculty of the Graduate School of Loyola University of Chicago in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy July 1988 ACKNOWLEDGMENTS The pursuit of a graduate degree is an endeavor impossible to undertake alone. My parents and family provided the love and nurture which guided me to adulthood, and my wife, Nancy, furnishes the love and encouragement which make life possible. This dissertation, as well as the honors which I have received, are as much theirs as they are mine. I owe the shaping of my development as a scientist to the rein- forcement and counsel of my advisor, Dr. Stanley A. Lorens. He has taught me never to be satisfied with mediocrity.