First published in 1943, Vitamins and Hormones is the longest-running serial published by Academic Press. The Series provides up-to-date information on vitamin and hormone research spanning data from molecular biology to the clinic. A volume can focus on a single molecule or on a disease that is related to vitamins or hormones. A hormone is interpreted broadly so that related substances, such as transmitters, cytokines, growth factors and others can be reviewed. This volume focuses on nociceptin opioid. - Expertise of the contributors- Coverage of a vast array of subjects- In depth current information at the molecular to the clinical levels- Three-dimensional structures in color- Elaborate signaling pathways
Front Cover 1
Nociceptin Opioid 4
Copyright 5
Contents 8
Contributors 12
Preface 16
Chapter 1: Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception 18
1. Nociception in Brief 19
1.1. Opioid receptor-like receptor—ORL-1 21
1.2. Nociceptin 24
1.3. Interrogating the activation and address domains of nociceptin(1-17) 26
2. Prospecting the Importance of the N-Terminal Tetrapeptide of Nociceptin(1-17) 28
3. Other Modifications to Nociceptin(1-17) 30
4. The Importance of Structure in Nociceptin Analogues 32
4.1. Importance of helicity 32
4.2. Other nociceptin derivatives 33
5. Recent Advances in ORL-1 Active Nociceptin Peptides 34
6. The Development of New Helix-Constrained Nociceptin Analogues 35
6.1. Design of helix-constrained nociceptin analogues 35
6.2. Helical structure of nociceptin(1-17)-NH2 analogues in water 36
6.3. Nuclear magnetic resonance spectra-derived structures 39
7. Biological Properties of Helical Nociceptin Mimetics 45
7.1. Cellular expression of ORL-1 and ERK phosphorylation 45
7.2. Agonist and antagonist activity of nociceptin(1-17)-NH2 and analogues 51
7.3. Effects of helical constraint on biological activity in Neuro-2a cells 57
7.4. Stability and cell toxicity of helix-constrained versus unconstrained peptides 60
7.5. In vivo activity of helix-constrained versus unconstrained nociceptin analogues 61
8. Concluding Remarks 63
References 63
Chapter 2: Bioinformatics and Evolution of Vertebrate Nociceptin and Opioid Receptors 74
1. Introduction 75
1.1. The origin of G protein-coupled receptors 76
1.2. A brief history of opioid receptors 77
1.3. Evidence for opioid receptors in nonmammalian vertebrates 80
2. The Vertebrate Opioid Receptor Sequence Database 82
2.1. Alignment of protein sequences 83
2.2. Phylogenetic analysis of vertebrate opioid receptors 86
2.3. Divergence and convergence of opioid receptor types 88
3. The Human Genome and the Evolution of Opioid Receptors 91
3.1. Duplicated opioid family receptor genes in the human genome 91
3.2. Variation in human opioid receptor genes 92
4. The Molecular Evolution of Vertebrate Opioid Family Receptors 96
5. Future Directions 98
6. Conclusions 100
Acknowledgments 101
References 101
Chapter 3: Ancestral Vertebrate Complexity of the Opioid System 112
1. Introduction 113
2. Opioid Peptide Family 117
3. Opioid Receptor Family 122
4. Discussion: Complexity, Coevolution, and Divergence 130
5. Conclusions 135
Acknowledgement 135
References 135
Chapter 4: Synthesis and Biological Activity of Small Peptides as NOP and Opioid Receptors' Ligands: View on Current Devel... 140
1. Introduction 141
2. Endogenous Opioid Peptides and Receptors: Nociceptin and NOP Receptor Ligands 143
3. Hexapeptides with NOP Receptor Affinity 150
4. Solid-Phase Peptide Synthesis 153
5. Conclusions 158
Acknowledgment 158
References 158
Chapter 5: Pain Regulation by Nocistatin-Targeting Molecules: G Protein-Coupled-Receptor and Nocistatin-Interacting Protein 164
1. Introduction 165
2. Biological Activity by NST Through G Protein-Coupled Receptor 169
2.1. Regulation of presynaptic neurotransmitter release through putative Gi/o-coupled NST receptor 169
2.2. Regulation of postsynaptic transmission through putative Gi/o-coupled NST receptor 170
2.3. Depolarization of projection neurons by a putative Gq/11-coupled NST receptor 171
3. Pain Regulation Through an NST-Interacting Protein 172
3.1. Purification of an NST-interacting protein using high-performance affinity latex nanobeads 172
3.2. Identification of NIPSNAP1 as an NST-interacting protein 173
3.3. Pain regulation induced by NIPSNAP1 174
3.4. Other functions of NIPSNAP1 176
4. Conclusions 177
Acknowledgment 178
References 178
Chapter 6: Nociceptin and Meiosis during Spermatogenesis in Postnatal Testes 184
1. Introduction 185
1.1. Meiotic chromosome dynamics during spermatogenesis 185
1.2. A role in spermatogenesis of FSH and the mechanism of its action 186
2. Regulation of Nociceptin Expression by FSH Signaling in Sertoli Cells 187
2.1. Phosphorylation of CREB following cAMP stimulation in a Sertoli cell line 187
2.2. Identification of prepronociceptin gene associating cAMP-dependently with phosphorylated CREB 189
2.3. Effects of cAMP and FSH on the expressions of prepronociceptin mRNA and the nociceptin peptide in Sertoli cells and ... 189
2.4. Expression of the endogenous nociceptin peptide in testes 190
3. Function of Nociceptin During Meiosis in Spermatocytes 190
3.1. The expression of endogenous Oprl-1 and the phosphorylation of endogenous Rec8 in testes 190
3.2. Effect of nociceptin on the phosphorylation of Rec8 in testes 191
3.3. Effect of nociceptin on the progress of meiosis during spermatogenesis 193
3.4. Effect of FSH on the phosphorylation of Rec8 in testes 194
4. Nociceptin is a Novel Paracrine Factor that is Induced in Sertoli Cells and Mediates to Germ Cells the Effect of FSH o... 195
4.1. Prepronociceptin gene is transcriptionally regulated by FSH signaling in Sertoli cells 195
4.2. Nociceptin is a paracrine factor mediating the FSH-regulated germ cell development 196
5. Nociceptin is a Novel Extrinsic Factor Inducing Rec8 Phosphorylation and Chromosome Dynamics During Meiosis in Spermat... 198
5.1. Nociceptin is an extrinsic regulator for Rec8 phosphorylation during meiosis in spermatocytes 198
5.2. Nociceptin is a testicular peptide, "testipeptide," that is expressed and functions locally within testes 200
6. Conclusions 200
Acknowledgments 201
References 201
Chapter 7: Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female 204
1. Introduction 206
2. Ovarian Hormone Regulation of Reproductive Behavior and Neuroendocrine Feedback Loops 207
2.1. Neuroendocrine feedback loops 207
2.2. Reproductive behavior 208
3. OFQ/N-ORL-1 Regulation of Sexual Receptivity 214
4. Ovarian Steroid Regulation of OFQ/N and ORL-1 Expression and Signaling 219
5. OFQ/N-ORL-1 Regulation of GnRH and LH Release During Positive and Negative Feedback 223
6. Conclusions 226
Acknowledgments 226
References 227
Chapter 8: Effects of Nociceptin and Nocistatin on Uterine Contraction 240
1. Roles of PNOC, N/OFQ, and NST in Different Peripheral Tissues 241
1.1. White blood cells 241
1.2. Airways 242
1.3. Liver 242
1.4. Skin 242
1.5. Vascular smooth muscle 243
1.6. Intestinal smooth muscle 243
1.7. Ovary 243
1.8. Testis 244
2. Presence of PNOC, N/OFQ, and NST in Uterine Tissue 244
2.1. PNOC in the uterus 245
2.2. N/OFQ and NST in the uterus 246
3. The Effects and Mechanisms of Action of N/OFQ and NST on Uterine Contractility 248
3.1. The effect of N/OFQ on uterine contractility 248
3.2. The effect of NST on uterine contractility 250
3.3. The combined effect of N/OFQ and NST on uterine contractility 252
4. Conclusions 252
References 254
Chapter 9: Nociceptin/Orphanin FQ-NOP Receptor System in Inflammatory and Immune-Mediated Diseases 258
1. A Brief Overview of the Immune Response 259
2. N/OFQ and Its Receptor 261
3. N/OFQ and NOP Receptor Expression in Leukocytes 262
4. Effects of NOP Receptor Activation on the Immune Response 262
5. NOP Receptor Activation and Inflammatory and Autoimmune Diseases 267
6. Molecular Mechanisms Underlying N/OFQ Actions on Immune Functions 272
7. Relationship Between N/OFQ, Stress, and HPA Axis 273
8. Conclusions 276
Acknowledgments 276
References 276
Chapter 10: Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior 284
1. Introduction 285
1.1. Nociceptin peptide and receptor system 285
1.2. Nociceptin and NOP receptor: Relevance to inflammation 286
1.3. Nociceptin and NOP receptor: Relevance to anxiety and stress 288
2. The Neuroanatomical Basis of Fear Conditioning 292
3. Evidence for a Role of Nociceptin in Fear Learning and Memory 293
4. Nociceptin and Neurochemical Substrates of Fear Conditioning: Focus on Biogenic Amines 294
5. Maternal Adaptations of the Nociceptin System 296
5.1. Maternal adaptations in neuroendocrine behavioral and stress responses 297
5.2. Prepartum adaptations and changes in N/OFQ expression and function 298
6. Conclusions 300
References 300
Chapter 11: The Neuronal Circuit Between Nociceptin/Orphanin FQ and Hypocretins/Orexins Coordinately Modulates Stress-Ind... 312
1. Introduction 313
2. The N/OFQ System 314
2.1. The discovery of N/OFQ 314
2.2. Complex modulation of nociceptive processing by N/OFQ 315
2.3. N/OFQ and the stress response 316
3. The Hypocretins/Orexins System 317
3.1. The discovery of Hcrts 317
3.2. Hcrt-induced analgesia 318
3.3. Hcrts and stress responses 319
4. Interaction Between the N/OFQ and Hcrt Systems 320
4.1. A local and direct neuronal circuit between N/OFQ- and Hcrt-producing neurons 321
4.2. Cellular physiological and pharmacological actions of N/OFQ on Hcrt neurons 323
4.3. Coordinated modulation of SIA 325
4.4. Coordinated modulation of anxiety-related behavior 328
5. Conclusions 330
Acknowledgments 333
References 333
Chapter 12: Nociceptin/Orphanin-FQ Modulation of Learning and Memory 340
1. Introduction 340
2. N/OFQ Modulation of Mnemonic Functions 342
2.1. N/OFQ modulation of spatial learning 342
2.2. N/OFQ modulation of fear learning and memory 346
2.2.1. Fear conditioning learning 347
2.2.2. Passive avoidance learning 349
2.3. N/OFQ modulation of recognition memory 351
2.4. N/OFQ modulation of working memory 352
2.5. N/OFQ modulation of sensorimotor gating 354
3. Mechanisms of N/OFQ-Mediated Modulation of Cognitive Functions 355
4. Conclusion and Remarks 357
Acknowledgments 358
References 358
Index 364
Color Plate 375
Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception
Rink-Jan Lohman1; Rosemary S. Harrison1; Gloria Ruiz-Gómez; Huy N. Hoang; Nicholas E. Shepherd; Shiao Chow; Timothy A. Hill; Praveen K. Madala; David P. Fairlie2 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
2 Corresponding author: email address: d.fairlie@imb.uq.edu.au
1 Joint first authors
Abstract
Nociceptin (orphanin FQ) is a 17-residue neuropeptide hormone with roles in both nociception and analgesia. It is an opioid-like peptide that binds to and activates the G-protein-coupled receptor opioid receptor-like-1 (ORL-1, NOP, orphanin FQ receptor, kappa-type 3 opioid receptor) on central and peripheral nervous tissue, without activating classic delta-, kappa-, or mu-opioid receptors or being inhibited by the classic opioid antagonist naloxone. The three-dimensional structure of ORL-1 was recently published, and the activation mechanism is believed to involve capture by ORL-1 of the high-affinity binding, prohelical C-terminus. This likely anchors the receptor-activating N-terminus of nociception nearby for insertion in the membrane-spanning helices of ORL-1. In search of higher agonist potency, two lysine and two aspartate residues were strategically incorporated into the receptor-binding C-terminus of the nociceptin sequence and two Lys(i) → Asp(i + 4) side chain–side chain condensations were used to generate lactam cross-links that constrained nociceptin into a highly stable α-helix in water. A cell-based assay was developed using natively expressed ORL-1 receptors on mouse neuroblastoma cells to measure phosphorylated ERK as a reporter of agonist-induced receptor activation and intracellular signaling. Agonist activity was increased up to 20-fold over native nociceptin using a combination of this helix-inducing strategy and other amino acid modifications. An NMR-derived three-dimensional solution structure is described for a potent ORL-1 agonist derived from nociceptin, along with structure–activity relationships leading to the most potent known α-helical ORL-1 agonist (EC50 40 pM, pERK, Neuro-2a cells) and antagonist (IC50 7 nM, pERK, Neuro-2a cells). These α-helix-constrained mimetics of nociceptin(1–17) had enhanced serum stability relative to unconstrained peptide analogues and nociceptin itself, were not cytotoxic, and displayed potent thermal analgesic and antianalgesic properties in rats (ED50 70 pmol, IC50 10 nmol, s.c.), suggesting promising uses in vivo for the treatment of pain and other ORL-1-mediated responses.
Keywords
Nociceptin
Nociception
Analgesia
ORL
Agonist
Helix
1 Nociception in Brief
Nociception is a term used to describe the ability of organisms to detect noxious stimuli (Wall & Melzack, 2000). It involves neural processing of external stimuli, signaling through receptors on neurons, that may damage the organism, enabling it to sense pain and take action to evade damage. In higher organisms, nociception is a series of exquisitely complex neural events involving neurons of the peripheral and central nervous system (CNS) that allow an organism to sense pain or algesia (Wall & Melzack, 2000). Noxious stimuli can be mechanical (pressure or sharp objects), thermal (temperatures above 45 °C or extreme cold), and chemical (acids, environmental irritants such as capsaicin), which are detected by an array of specialized receptors (termed nociceptors) on the terminals of spinal nerve afferents that have their cell bodies in ganglia positioned outside of the spinal cord. These pain-sensing neurons (canonically unmyelinated, slow conduction velocity C-fibers and myelinated moderate conduction velocity Aδ-fibers) are generally considered part of the peripheral nervous system and send signals after detection of noxious stimuli via their extraspinal ganglia to the dorsal horn of the spinal cord en route to the brain for processing of conscious pain perception (Wall & Melzack, 2000). This ultimately allows the organism to act to avoid further damage by removing itself from the noxious stimuli or cause tissue injury, and allow healing. To add to the complexity, the initial response to pain avoidance is usually considered a reflex action, with the withdrawal response not initially involving the brain (Wall & Melzack, 2000).
Aside from the classical descriptions of pain in uninjured tissue via specialized nociceptors globally referred to as mechanoceptors, thermoceptors, and chemoceptors (with obvious nomenclature), pain can be promoted by endogenous inflammatory mediators released from various inflammatory cells (Wall & Melzack, 2000). These mediators are detected by diverse classes of chemoceptors that respond to many exogenous and endogenous chemicals, including histamine (Harasawa, 2000; Rosa & Fantozzi, 2013) (H1 receptors: Akdis & Simons, 2006; possibly others, H2: Hasanein, 2011; Mobarakeh et al., 2005; and H3: Cannon & Hough, 2005; Smith, Haskelberg, Tracey, & Moalem-Taylor, 2007), neuropeptides (Abrams & Recht, 1982) such as substance P (Munoz & Covenas, 2011), enkephalins (Bodnar, 2013), and bradykinins (Jaggi & Singh, 2011; Maurer et al., 2011) via various receptors including the NK1 and transient receptor potential channel families (Brederson, Kym, & Szallasi, 2013; Salat, Moniczewski, & Librowski, 2013). Even various proteases (such as tryptase) acting at protease-activated receptors (Bao, Hou, & Hua, 2014; Bunnett, 2006; Vergnolle et al., 2001) can signal pain. These substances via their receptors can contribute to a heightened pain sensation, referred to as hyperalgesia, which describes when a normally painful stimulus becomes excessively painful. However, if persistent it can lead to allodynia, when a normally nonpainful stimulus becomes painful to the individual (Wall & Melzack, 2000). These can both be symptoms of normal inflammatory pain and can be of benefit to an organism by warning the individual of tissue damage. However, when pain becomes chronic, it can seriously interfere with the quality of life of the individual, leading to significant morbidity. Such pain is considered neuropathic if it becomes either ongoing or episodic in nature, the cause of which may be in absence of a known or precipitating inflammatory condition or lesion. Such chronic pain is commonly treated with opiates, a name given to a family of alkaloids, such as morphine or codeine, derived from the opium poppy (Papaver somniferum), or their synthetic counterparts, the opioids, all of which act through G-protein-coupled receptors of the opioid receptor family (delta (δ1–2), kappa (κ1–3), and mu (μ1–3); Wall & Melzack, 2000). However, the actions of the opiate alkaloids at their receptors can produce significant and unwanted effects such as respiratory depression, physical dependence, sedation, hallucinations, and other dissociative effects that may significantly impact on an individual's well-being and contribution to society if taken for extended periods, as generally required for chronic pain sufferers. Likewise, once they are no longer needed due to resolution of the condition, withdrawal symptoms precipitated by their dependence effects may result, and these are not only unpleasant, but can be devastating to patients and their families if dependence becomes abuse. This limits their effectiveness as drugs for the greater population, and thus there is a requirement for potent antinociceptive compounds that target the opioid receptors without the side effects of the classical alkaloid opiates.
1.1 Opioid receptor-like receptor—ORL-1
A relatively recent addition to the GPCR opioid receptor family is the opioid receptor-like-1 (ORL-1 or NOP) receptor (Fig. 1). It was named because of high homology with the classical opioid receptors, but it was not affected by classical opioid receptor antagonists such as naloxone. The “orphan” receptor ORL-1 was initially identified from mRNA transcripts taken from mouse and rat CNSs, and deorphanized with the discovery of nociceptin as an endogenous ligand (Bunzow et al., 1994; Chen et al., 1994; Meunier et al., 1995; Mollereau et al., 1994; Salvadori, Guerrini, Calo, & Regoli, 1999; Wang et al., 1994; Wick, Minnerath, Roy, Ramakrishnan, & Loh, 1995). The location of the ORL-1 receptor has since been confirmed, and receptor-binding assays and in situ hybridization techniques have been used to pinpoint ORL-1 to the cortex, anterior olfactory nucleus, lateral septum, hypothalamus, hippocampus, amygdala, and other regions of the brain. Interestingly, ORL-1 transcripts have also been identified in nonneuronal peripheral organs such as intestine, vas deferens, kidney, and the spleen (Osinski, Pampusch, Murtaugh, & Brown, 1999; Wang et al., 1994) and in unexpected cell types, such as mouse sphenic lymphocytes (Halford, Gebhardt, & Carr, 1995) as...
| Erscheint lt. Verlag | 6.2.2015 |
|---|---|
| Mitarbeit |
Herausgeber (Serie): Gerald Litwack |
| Sprache | englisch |
| Themenwelt | Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie |
| Naturwissenschaften ► Biologie ► Biochemie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| Naturwissenschaften ► Biologie ► Zoologie | |
| Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik | |
| Technik | |
| ISBN-10 | 0-12-802593-X / 012802593X |
| ISBN-13 | 978-0-12-802593-2 / 9780128025932 |
| Haben Sie eine Frage zum Produkt? |
PDF (Adobe DRM)Größe: 14,9 MB
Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: PDF (Portable Document Format)
Mit einem festen Seitenlayout eignet sich die PDF besonders für Fachbücher mit Spalten, Tabellen und Abbildungen. Eine PDF kann auf fast allen Geräten angezeigt werden, ist aber für kleine Displays (Smartphone, eReader) nur eingeschränkt geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
EPUB (Adobe DRM)Größe: 13,0 MB
Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: EPUB (Electronic Publication)
EPUB ist ein offener Standard für eBooks und eignet sich besonders zur Darstellung von Belletristik und Sachbüchern. Der Fließtext wird dynamisch an die Display- und Schriftgröße angepasst. Auch für mobile Lesegeräte ist EPUB daher gut geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
aus dem Bereich
