WJNS  Vol.4 No.4 , August 2014
Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?
Author(s) Margit Pissarek*

Neuropeptide receptors of the brain and spinal cord are parts of the pain circuits targeted by analgesic drugs. Some of these receptors have been found in the central nervous system as well as in intracranial vascular structures and achieved revival of attention because of their role in acute and chronic pain syndromes. A number of them are of high clinical relevance for e.g. migraine. Others participate in symptoms of rare diseases like amyotrophic lateral sclerosis. Here we will focus on five of the neuropeptide receptors and their non-peptide ligands potentially or already successfully used as PET probes. Opioid receptors and neurotensin receptors are known to mediate analgesic actions. Bradykinin and calcitonin gene-related peptide (CGRP) receptors are known to be involved in the regulation of vascular tone and inflammatory responses, and neurokinin receptors play a role in the occurrence of pain perception in a rather indirect manner. Most experiences as PET tracers have been gathered with opioid receptor ligands and neurokinin receptor ligands. The most innovative fields revealed by the studies summarized in this report are the ligands of κ opioid receptors and CGRP receptors for which a first PET tracer was presented recently.

Cite this paper
Pissarek, M. (2014) Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?. World Journal of Neuroscience, 4, 353-383. doi: 10.4236/wjns.2014.44040.
[1]   MaassenVanDenBrink, A. and Chan, K.Y. (2008) Neurovascular Pharmacology of Migraine. European Journal of Pharmacoloy, 585, 313-319. http://dx.doi.org/10.1016/j.ejphar.2008.02.091

[2]   Vecchia, D. and Pietrobon, D. (2012) Migraine: A Disorder of Brain Excitatory-Inhibitory Balance? Trends in Neurosciences, 35, 507-520. http://dx.doi.org/10.1016/j.tins.2012.04.007

[3]   Charcot, J.M. (1877) Lectures on Diseases of the Nervous System. The New Sydenham Society, London, 137.

[4]   Charcot, J.M. (1892) De la Maladie de Morvan. Sciatique ancienne avec atrophie musculaire et troubles de la sensibilité. In: Babé, V.V. and Guinon, G., Eds., Clinique des maladies du systéme nerveux, Tome I, Progres Medical, Paris, 155.

[5]   Handy, C.R., Krudy, C., Boulis, N. and Federici, T. (2011) Pain in Amyotrophic Lateral Sclerosis: A Neglect Aspect of Disease. Neurology Research International, 2011, Article ID: 403808.

[6]   Winkler, E.A., Sengillo, J.D., Sullivan, J.S., Henkel, J.S., Appel, S.H. and Zlokovic, B.V. (2013) Blood-Spinal Cord Barrier Breakdown and Pericyte Reductions in Amyotrophic Lateral Sclerosis. Acta Neuropathologica, 125, 111-120.

[7]   Hunzinga, M.M. and Peltier, A. (2007) Painful Diabetic Neuropathy: A Management Centered Review. Clinical Diabetes, 25, 6-15. http://dx.doi.org/10.2337/diaclin.25.1.6

[8]   Rosso, M., Munoz, M. and Berger, M. (2012) The Role of Neurokinin-Receptor in the Microenvironment of Inflammation and Cancer. Scientific World Journal, 2012, Article ID: 381434.

[9]   Edvinsson, L., Villalon, C.M. and MaasssenVanDenBrink, A. (2012) Basic Mechanisms of Migraine and Its Acute Treatment. Pharmacology & Therapeutics, 136, 319-333.

[10]   Dobner, P.R. (2006) Neurotensin and Pain Modulation. Peptides, 27, 2405-2414.

[11]   Fichna, J., Janecka, A., Costentin, J. and Do Rego, J.C. (2007) The Endomorphin System and Its Evolving Neurophysiological Role. Pharmacological Reviews, 59, 88-123. http://dx.doi.org/10.1124/pr.59.1.3

[12]   Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B. and Garcia-Larrea, L. (2007) Differential Brain Opioid Receptor Availability in Central and Peripheral Neuropathic Pain. Pain, 127, 183-194.

[13]   Leavitt, S.B. (2009) Opioid Antagonists, Naloxone & Naltrexone-Aids for Pain Management. Pain Treatment Topics, pai-topics.org, Glenview, 1-16.

[14]   LaFrance, M., Roussy, G., Belleville, K., Maeno, H., Beaude, N., Wada, K. and Sarret, P. (2010) Involvement of NTS2 Receptors in Stress-Induced Analgesia. Neuroscience, 166, 639-652.

[15]   Shulman, J.M. and Strichartz, G.R. (2008) Local Anesthetic Pharmacology. In: Golan, D.E., Tashjian Jr., A.H., Armstrong, E.J. and Armstrong, A.W., Eds., Principles of Pharmacology, 2nd Edition, Wolters Kluwer, Lippincott Williams & Wiilkins, Philadelphia, 145-160.

[16]   Henriksen, G. and Willoch, F. (2008) Imaging of Opioid Receptors in the Central Nervous System. Brain, 131, 1171-1196. http://dx.doi.org/10.1093/brain/awm255

[17]   Malherbe, P., Bissantz, C., Marcuz, A., Kratzeisen, C., Zenner, M.T., Wettstein, J.G., Ratni, H., Riemer, C. and Spooren, W. (2008) Me-Talnetant and Osanetant Interact with Overlapping but Not Identical Binding Pockets in the Human tachykinin Neurokinin 3 Receptor Transmembrane Domains. Molecular Pharmacology, 73, 1736-1750.

[18]   Aziz, F. (2012) Neurokinin-1 Receptor Antagonists for Chemotherapy-Induced Nausea and Vomiting. Annals of Palliative Medicine, 1, 130-136.

[19]   Gurevich, E.V., Tesmer, J.J., Mushegian, A. and Gurevich, V.V. (2012) G-Protein Coupled Receptor Kinases: More than Just Kinases and Not Only for GPCRS. Pharmacology & Therapeutics, 133, 40-69.

[20]   Rajagopal, S., Rajagopal, K. and Lefkowitz, R.J. (2010) Teaching Old Receptors New Tricks: Biasing Seven-Transmembrane Receptors. Nature Reviews Drug Discovery, 9, 373-386.

[21]   Milan-Lobo, L. and Whistler, J.L. (2011) Heteromerization of the μ-and δ-Opioid Receptors Produces Ligand-Biased Antagonism and Alters μ-Receptor Trafficking. Journal of Pharmacology and Experimental Therapeutics, 337, 868-875. http://dx.doi.org/10.1124/jpet.111.179093

[22]   Lefkowitz, R.J. (2013) A Brief History of G-Protein Coupled Receptors (Nobel Lecture). Angewandte Chemie International Edition, 52, 6367-6378. http://dx.doi.org/10.1002/anie.201301924

[23]   Shukla, A.K., Manglik, A., Kruse, A.C., Xiao, K., Reis, R., Tseng, W.C., Staus, D.P., Hilger, D., Uysal, S., Huang, L.Y., Paduch, M., Tripathi-Shukla, P., Koide, A., Koide, S., Weis, W.I., Kossiakoff, A.A., Kobilka, B.K. and Lefkowitz, R.J. (2013) Structure of Active β-Arrestin-1 Bound to a G-Protein-Coupled Receptor Phosphopeptide. Nature, 497, 137-142. http://dx.doi.org/10.1038/nature12120

[24]   Bohn, L.M., Dykstra, L.A., Lefkowitz, R.J., Caron, M.G. and Barak, L.S. (2004) Relative Opioid Efficacy Is Determined by the Complements of the G Protein-Coupled Receptor Desensitization Machinery. Molecular Pharmacology, 66, 106-112. http://dx.doi.org/10.1124/mol.66.1.106

[25]   Raehal, K.M., Walker, J.K. and Bohn, L.M. (2005) Morphine Side Effects in β-Arrestin 2 Knockout Mice. Journal of Pharmacology and Experimental Therapeutics, 314, 1195-1201.

[26]   Groer, C.E., Tidgewell, K., Moyer, R.A., Harding, W.W., Rothman, R.B., Prisinzano, T.E. and Bohn, L.M. (2007) An Opioid Agonist That Does Not Induce μ-Opioid Receptor-Arrestin Interactions or Receptor Internalization. Molecular Pharmacology, 71, 549-557. http://dx.doi.org/10.1124/mol.106.028258

[27]   Venkatakrishnan, A.J., Deupi, X., Lebon, G., Tate, C., Schertler, G.F. and Babu, M.M. (2013) Molecular Signatures of G-Protein-Coupled Receptors. Nature, 494, 185-194.

[28]   Albizu, L., Moreno, J.L., Gonzalez-Maeso, J. and Sealfon, S.C. (2010) Heteromerization of G-Protein-Coupled Receptors: Relevance to Neurological Disorders and Neurotherapeutics. CNS & Neurological Disorders-Drug Targets, 9, 636-650. http://dx.doi.org/10.2174/187152710793361586

[29]   Fuxe, K., Marcellino, D., Borroto-Escuela, D.O., Frankowska, M., Ferraro, L., Guidolin, D., Ciruela, F. and Agnati, L.F. (2010) The Changing World of G Protein-Coupled Receptors: From Monomers to Dimers and Receptor Mosaics with Allosteric Receptor-Receptor Interactions. Journal of Receptors and Signal Transduction, 30, 272-283.

[30]   Rasmussen, S.G.F., Choi, H.J., Rosenbaum, D.M., Kobilka, T.S., Thian, F.S., Edwards, P.C., Burghammer, M., Ratnala, V.R.P., Sanishvili, R., Fischetti, R.F., Schertler, G.F., Weis, W. and Kobilka, B.K. (2007) Crystal Structure of the Human β2 Adrenergic G-Protein Coupled Receptor. Nature, 450, 383-387.

[31]   Jordan, B.A. and Devi, L.A. (1999) G-Protein-Coupled Receptor Heteromerization Modulates Receptor Function. Nature, 399, 697-700. http://dx.doi.org/10.1038/21441

[32]   George, S.R., Fan, T., Xie, Z., Tse, R., Tam, V., Varghese, G. and O’Dowd, B.F. (2000) Oligomerization of μ and δ-Opioid Receptors: Generation of Novel Functional Properties. Journal of Biological Chemistry, 275, 26128-26135.

[33]   Borroto-Escuela, D.O., Romero-Fernandez, W., Rivera, A., van Craenenbroeck, K., Tarakanov, A.O., Agnati, L.F. and Fuxe, K. (2013) On the G-protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation. Evidence-Based Complementary and Alternative Medicine, 2013, Article ID: 563716.

[34]   Chakrabarti, S., Liu, N. J.and Gintzler, A.R. (2010) Formation of μ/κ Opioid Receptor Heterodimer Is Sex Dependent and Mediates Female-Specific Opioid Analgesia. Proceedings of the National Academy of Sciences of the United States of America, 107, 20115-20119.

[35]   Vilardaga, J.P., Nikolaev, O.V., Lorentz, K., Ferrandon, S., Zhuang, Z. and Lohse, M.J. (2008) Direct Inhibition of G-Protein Signaling by Cross Conformational Switches between α2a Adrenergic and μ Opioid Receptors. Nature Chemical Biology, 4, 126-131. http://dx.doi.org/10.1038/nchembio.64

[36]   Vilardaga, J.P., Agnati, L.F., Fuxe, K. and Ciruela, F. (2010) G-Protein-Coupled Receptor Heteromer Dynamics. Journal of Cell Science, 123, 4215-4220. http://dx.doi.org/10.1242/jcs.063354

[37]   Smith, N.J. and Milligan, G. (2010) Allostery at G-Protein-Coupled Receptor Homo-and Heteromers: Uncharted Pharmacological Landscapes. Pharmacological Reviews, 62, 701-725.

[38]   Dickenson, A.H. (1995) Spinal Cord Pharmacology of Pain. British Journal of Anaesthesia, 75, 193-200.

[39]   Craik, D.J., Fairlie, D.P., Liras, S. and Price, D. (2013) The Future of Peptide-Based Drugs. Chemical Biology Drug Design, 81, 136-147.

[40]   Bartanusz, V., Jezova, D., Alajajian, B. and Digicaylioglu, M. (2011) The Blood-Spinal Cord Barrier: Morphology and Clinical Implications. Annals of Neurology, 70, 194-206.

[41]   Xanthos, D.N., Püngel, I., Wunderbaldinger, G. and Sandkühler, J. (2012) Effects of Peripheral Inflammation of the Blood-Spinal Cord Barrier. Molecular Pain, 8, 44. http://dx.doi.org/10.1186/1744-8069-8-44

[42]   Naliboff, B.D., Munokata, J., Fullerton, S., Gracely, R.H., Kodner, A., Harraf, F. and Mayer, E.A. (1997) Evidence for Two Distinct Perceptual Alterations in Irritable Bowl Syndrome. Gut, 41, 505-512.

[43]   Okano, S., IKeura, Y. and Inatomi, N. (2002) Effects of Tachikinin NK1 Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits. Journal of Pharmacology and Experimental Therapeutics, 300, 925-931. http://dx.doi.org/10.1124/jpet.300.3.925

[44]   Griffante, C., Carletti, R., Andreetta, F. and Corsi, M. (2006) [3H] GR205171 Displays Similar NK1 Receptor Binding Profile in Gerbils and Human Brain. British Journal of Pharmacology, 148, 39-45.

[45]   Gaddum, J.H. and Schild, H. (1935) Depressor Substances in Extracts of Intestine. Journal of Physiology (London), 83, 1-14.

[46]   von Euler, U.S.V. and Gaddum, J.H. (1931) An Unidentified Depressor Substance of the Dog. The Journal of Physiology, 72, 74-87.

[47]   von Euler, U.S.V. and Pernow, B. (1954) Effects of Intraventricular Administration of Substance P. Nature, 174, 184.

[48]   Willoch, F., Schindler, F., Wester, H.J., Empl, M., Straube, A., Schwaiger, M., Conrad, B. and Tolle, T.R. (2004) Central Poststroke Pain and Reduced Opioid Receptor Binding within Pain Processing Circuitries: A [11C] Diprenorphine PET Study. Pain, 108, 213-220. http://dx.doi.org/10.1016/j.pain.2003.08.014

[49]   Sprenger, T., Valet, M., Boecker, H., Henriksen, G., Spilker, M.E., Willoch, F., Wagner, K.J., Wester, H.J. and Tolle, T.R. (2006) Opioidergic Activation in the Medial Pain System after Heat Pain. Pain, 122, 63-67.

[50]   Maarrawi, J., Peyron, R., Mertens, P., Costes, N., Magnin, M., Sindou, M., Laurent, B. and Garcia-Larrea, L. (2007) Differential Brain Opioid Receptor Availability in Central and Peripheral Neuropathicpain. Pain, 127, 183-194.

[51]   Henriksen, G. and Willoch, F. (2008) Imaging of Opioid Receptors in the Central Nervous System. Brain, 131, 1171-1196. http://dx.doi.org/10.1093/brain/awm255

[52]   Sprouse-Blum, A.S., Smith, G., Sujai, D. and Don Parsa, F. (2010) Understanding Endorphins and Their Importance in Pain Management. Hawai Medical Journal, 69, 70-71.

[53]   Brooks, D.J. (2010) Imaging Approaches to Parkinson Disease. Journal of Nuclear Medicine, 51, 596-609.

[54]   Kleczkowska, P. and Lipkowski, A.W. (2013) Neurotensin and Neurotensin Receptors: Characteristic Structure-Activity Relationship and Pain Modulation—A Review. European Journal of Pharmacology, 716, 54-60.

[55]   Hoyer, D. and Bartfai, T. (2012) Neuropeptides and Neuropeptide Receptors: Drug Targets and Peptide and Non-Peptide Ligands: A Tribute to Prof. Dieter Seebach. Chemistry and Biodiversity, 9, 2367-2387.

[56]   Maurer, M., Bader, M., Bas, M., Bossi, F., Cicardi, M., Cugno, M., Howarth, P., Kaplan, A., Kojda, G, Leeb-Lundberg, F., Lotvall, J. and Magerl, M. (2011) New Topics in Bradykinin Research. Allergy, 66, 1397-1406.

[57]   Benemei, S., Nicoletti, P., Capone, J.G. and Geppetti, P. (2009) CGRP Receptors in the Control of Pain and Inflammation. Current Opinion in Pharmacology, 9, 9-14.

[58]   Dam, T.V., Martinelli, B. and Quirio, R. (1990) Autoradiographic Distribution of Brain Neurokinin-1/Substance P Receptors Using a Highly Selective Ligand [3H]-[Sar9, Met (O2)11]-Substance P. Brain Research, 531, 333-337.

[59]   Tousignant, C., Guillemette, G., Drapeau, G., Telemaque, S., Dion, S. and Regoli, D. (1990) 125I-BH[Sar9, Met (O2)11]-SP, a New Selective Ligand for the NK-1 Receptor in the Central Nervous System. Brain Research, 524, 263-270.

[60]   Bell, I.M., Gallichio, S.N., Stump, C.A., Bruno, J.G., Fan, H., Gantert, L.T., Hostetler, E.D., Kemmerer, A.L., McWherter, M., Moore, E.L., Mosser, S.D., Purcell, M.L., Riffel, K., Salvatore, C.A., Sanabria-Bohorquez, S., Staas, D.D., White, R.B., Williams, M., Zartmann, C.B., Cook, J.J., Hargreaves, R.J., Kane, S.A., Graham, S.L. and Selnick, H.G. (2013) [11C]-MK-4232: The First Positron Emission Tomography Tracer for the Calcitonin Gene-Related Peptide Receptor. ACS Medicinal Chemistry Letters, 4, 863-868. http://dx.doi.org/10.1021/ml400199p

[61]   Lord, J.A., Waterfield, A.A., Hughes, J. and Kosterlitz, H.W. (1977) Endogenous Opioid Peptides: Multiple Agonists and Receptors. Nature, 267, 495-499. http://dx.doi.org/10.1038/267495a0

[62]   Simon, E.J., Hiller, J.M. and Edelman, I. (1973) Stereospecific Binding of the Potent Narcotic Analgesic (3H) Etorphine to Rat Brain Homogenate. Proceedings of the National Academy of Sciences of the United States of America, 70, 1947-1951. http://dx.doi.org/10.1073/pnas.70.7.1947

[63]   Pert, C.B. and Snyder, S.H. (1973) Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain. Science, 179, 1011-1014. http://dx.doi.org/10.1126/science.179.4077.1011

[64]   Terenius, L. (1973) Stereospecific Interaction between Narcotic Analgesics and a Synaptic Plasma Membrane Fraction of Rat Cerebral Cortex. Acta Pharmacologica et Toxicologica, 32, 317-320.

[65]   Bunzow, J.R., Saez, C., Mortrud, M., Bouvier, C., Williams, J.T., Low, M. and Grandy, D.K. (1994) Molecular Cloning and Tissue Distribution of a Putative Member of the Rat Opioid Receptor Gene Family that Is Not a μ, δ or κ Opioid Receptor Type. FEBS Letters, 347, 284-288.

[66]   Kieffer, B.L., Befort, K., Gaveriaus-Ruff, C. and Hirth, C.G. (1992) The Delta-Opioid Receptor: Isolation of a cDNA by Expression Cloning and Pharmacological Characterization. Proceedings of the National Academy of Sciences of the United States of America, 89, 12048-12052.

[67]   Evans, C.J., Keith, D.E., Morrison, H., Magendzo, K. and Edwards, R.H. (1992) Cloning of a Delta Opioid Receptor by Functional Expression. Science, 258, 1952-1955. http://dx.doi.org/10.1126/science.1335167

[68]   Davis, M.P. and Pasternak, G.W. (2009) Opioid Receptors and Opioid Pharmacodynamics.In: Davis, M.P., Glare, P.A., Hardy, J. and Quingley, C., Eds., Chapter 1, Opioids in Cancer Pain, 2nd Edition, Oxford University Press, Oxford, 1-24.

[69]   Manglik, A., Kruse, A., Kobilka, T.S., Thian, F.S., Mathiesen, J.M., Sunahara, R.K., Pardo, L., Weis, W.I., Kobilka, B.K. and Granier, S. (2012) Crystal Structure of the μ-Opioid Receptor Bound to a Morphinan Antagonist. Nature, 485, 321-327. http://dx.doi.org/10.1038/nature10954

[70]   Stein, C. (1995) Mechanism of Disease: The Control of Pain in Peripheral Tissue by Opioids. The New England Journal of Medicine, 332, 1685-1690. http://dx.doi.org/10.1056/NEJM199506223322506

[71]   Ingram, S.L. and Williams, J.T. (1994) Opioid Inhibition of Ih via Adenylyl Cyclase. Neuron, 13, 179-186.

[72]   Ikeda, K., Kobayashi, T., Ichikawa, T, Kumanishi, T., Niki, H. and H., Yano, R. (2001) The Untranslated Region of μ-Opioid Receptor mRNA Contributes to Reduced Opioid Sensitivity in CXBK Mice. The Journal of Neuroscience, 21, 1334-1339.

[73]   Law, P.Y., Wong, Y.H. and Loh, H.H. (2000) Molecular Mechanisms and Regulation of Opioid Receptor Signaling. Annual Review of Pharmacology and Toxicology, 40, 389-430.

[74]   Ishikawa, M. and Hashimoto, K. (2010) The Role of Sigma-I Receptors in the Pathophysiology of Neuropsychiatric Diseases. Journal of Receptor, Ligand and Channel Research, 3, 25-36.

[75]   Hayashi, T. and Su, T.P. (2007) Sigma-1 Receptor Chaperones at the ER-Mitochondrion Interface Regulates Ca2+ Signaling and Cell Survival. Cell, 131, 596-610. http://dx.doi.org/10.1016/j.cell.2007.08.036

[76]   Gundlach, A.L., Largent, B.L. and Snyder, S.H. (1986) Autoradiographic localization of Sigma Receptor Binding Sites in Guinea Pig and Rat Central Nervous System with (+)3H-3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine. The Journal of Neuroscience, 6, 1757-1770.

[77]   Quirion, R., Chicheportiche, R., Contreras, P.C., Johnson, K.M., Lodge, D., Tam, S.W., Woods, J.H. and Zukin, S.R. (1987) Classification and Nomenclature of Phencyclidine and Sigma Receptor sites. Trends in Neurosciences, 10, 444-446. http://dx.doi.org/10.1016/0166-2236(87)90094-4

[78]   Moebius, F.F., Reiter, R.J., Hanner, M. and Glossmann, H. (1997) High Affinity of Sigma1 Binding Sites for Sterol Isomerization Inhibitors: Evidence for a Pharmacological Relationship with the Yeast Sterol C8-C7 Isomerase. British Journal of Pharmacology, 121, 1-6. http://dx.doi.org/10.1038/sj.bjp.0701079

[79]   Law, P.Y., Loh, H.H. and Li, C.H. (1979) Properties and Localization of Endorphin Receptor in Rat Brain. Proceedings of the National Academy of Sciences of the United States of America, 76, 5455-5459.

[80]   Czlonkowski, A., Costa, T., Przewlocki, R., Pasi, A. and Herz, A. (1983) Opiate Receptor Binding Sites in Human spinal Cord. Brain Research, 267, 392-396. http://dx.doi.org/10.1016/0006-8993(83)90897-1

[81]   Besse, D., Lombard, M.C., Zajac, .M., Roques, B.P. and Besson, J.M. (1990) Pre-and Postsynaptic Distribution of μ, δ and κ Opioid Receptors in the Superficial Layers of the Cervical Dorsal Horn of the Rat Spinal Cord. Brain Research, 521, 15-22. http://dx.doi.org/10.1016/0006-8993(90)91519-M

[82]   Faull, R.L.M. and Villinger, J.W. (1987) Opiate Receptors in the Human Spinal Cord: A Detailed Anatomical Study Comparing the Autoradiographic Localization of [3H] Diprenorphine Binding Sites with the Laminar Pattern of Substance P, Myelin and Nissl Staining. Neuroscience, 20, 395-407.

[83]   Hiller, J.M. and Fan, L.Q. (1996) Laminar Distribution of the Multiple Opioid Receptors in Human Cerebral Cortex. Neurochemical Research, 21, 1333-1345.

[84]   Kitchen, I., Slowe, S.J., Matthes, H.W.D. and Kieffer, B. (1997) Quantitative Autoradiographic Mapping of μ-, δ-and κ-Opioid Receptors in Knockout Mice Lacking the μ-Opioid Receptor Gene. Brain Research, 778, 73-88.

[85]   Takemori, A.E. and Portoghese, P.S. (1985) Affinity Labels for Opioid Receptors. Annual Review of Pharmacology and Toxicology, 25, 193-223.

[86]   Broadbear, J.H., Sumpter, T.L., Burke, T.F., Husbands, S.M., Lewis, J.W., Woods, J.H. and Traynor, T.F. (2000) Methocinnamox Is a Potent, Long-Lasting, and Selective Antagonist of Morphine Mediated Antinociception in the Mouse: Comparison with Clocinnamox, β-Funaltrexamin, and β-Chlornatrexamine. Journal of Pharmacology and Experimental Therapeutics, 294, 933-940.

[87]   Hahn, F.F. and Pasternak, G.W. (1981) Naloxazine, a Potent, Long-Lasting Inhibitor of Opiate Binding Sites. Life Sciences, 31, 1385-1388. http://dx.doi.org/10.1016/0024-3205(82)90387-3

[88]   Porthogese, P.S., Lipkowski, A.W. and Takemori, A.E. (1987) Binaltorphimine and Nor-Binaltorphimine, Potent and Selective κ Opioid Receptor Antagonists. Life Science, 40, 1287-1292.

[89]   Neumann, G., Erhardt, W., Oberhuber, B., Fritsch, R. and Blumel, G. (1980) A New Highly Potent and Short-Acting Analgesic, Carfentanyl (R 33799), in Combination with the Hypnotic Agent, Etomidat (R 26490), as a Method of Anesthesia in Guinea Pigs. Zeitschrift für die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie, 177, 135-143.

[90]   Frost, J.J., Douglass, K.H., Mayberg, H.S., Dannals, R.F., Links, J.M., Wilson, A.A., Ravert, H.T., Crozier, W.C. and Wagner, H.N. (1989) Multicompartmental Analysis of [11C]-Carfentanil Binding to Opiate Receptors in Humans Measured by Positron Emission Tomography. Journal of Cerebral Blood Flow & Metabolism, 9, 398-409.

[91]   Guterstam, J., Jayram-Lindstrom, N., Cervenka, S., Frost, J.J. and Farde, L. (2013) Effects of Amphetamine on the Human Brain Opioid System—A Positron Emission Tomography Study. The International Journal of Neuropsychopharmacology, 16, 763-769.

[92]   Burke, T.R., Rice, K.C. and Pert, C.B. (1985) Probes for Narcotic Receptor Mediated Phenomena. II. Synthesis of 17-Methyl and 17-Cyclopropylmethyl-3,14-Dihydroxy-4,5Alpha-Epoxy-6-Beta-Fluoromorphinans (Foxy and Cyclofoxy) as Models of Opioid Ligands Suitable for Positron Emission Transaxial Tomography. Heterocycles, 23, 99-106.

[93]   Kling, M., Borg, L., Zametkin, A., Schluger, J., Carson, R., Matochik, J., Maslansky, R., Khuri, R., Wells, A., Lambert, S., Kreuter, J., Herscovitch, P., Eckelman, W., Rice, K., Ho, A. and Kreek, M.J. (1997) Opioid Receptor Binding in Methadone Maintained Former Heroin Addicts by PET Imaging Using [18F]Cyclofoxy. NIDA Research Monograph, 174, 120.

[94]   Pert, C.B., Danks, J.A., Channing, M.A., Eckelman, W.C., Larson, S.M., Bennett, J.M., Burke Jr., T.R. and Rice, K.C. (1984) 3-[18F]Acetylcyclofoxy: A Useful Probe for the Visualization of Opiate Receptors in Living Animals. FEBS Letters, 177, 281-286. http://dx.doi.org/10.1016/0014-5793(84)81300-9

[95]   Theodore, W.H., Carson, R.E., Andreasen, P., Zametkin, A., Blasberg, R. and Leiderman, D.B. (1992) PET Imaging of Opiate Receptor Binding in Human Epilepsy Using [18F]Cyclofoxy. Epilepsy Research, 13, 129-139.

[96]   Lever, J.R. (2007) PET and SPECT Imaging of the Opioid System: Receptors Radioligands and Avenues for Drug Discovery and Development. Current Pharmaceutical Design, 13, 33-49.

[97]   Naylor, M.R., Seminowicz, D.A., Somers, T.J. and Keefe, F.J. (2012) Pain Imaging. In: Moore, R.J., Ed., Chapter 27, Handbook of Pain and Palliative Care, Springer Science Buisiness Media, LLC, New York, Dordrecht, Heidelberg, London, 439-467.

[98]   Poisnel, G., Queslati, F., Dhilly, M., Delamare, J., Perrio, C., Debruyne, D. and Barre, L. (2008) [11C]-MeJDTic: A Novel Radioligand for κ-Opioid Receptor Positron Emission Tomography Imaging. Nuclear Medicine and Biology, 35, 561-569. http://dx.doi.org/10.1016/j.nucmedbio.2008.02.010

[99]   Goody, R.J., Oakley, S.M., Filliol, D., Kieffer, B.L. and Kitchen, I. (2002) Quantitative Autoradiographic Mapping of Opioid Receptors in the Brain of δ-Opioid Receptor Gene Knockout Mice. Brain Research, 945, 9-19.

[100]   Endres, C.J., Bencherif, B., Hilton, J., Madar, I. and Frost, J.J. (2003) Quantification of Brain μ-Opioid Receptors with [11C]Carfentanil: Reference-Tissue Methods. Nuclear Medicine and Biology, 30, 177-186.

[101]   Hammers, A. and Lingford-Hughes, A. (2006) Opioid Imaging. Neuroimaging Clinics of North America, 16, 529-552.

[102]   Jones, R.M. and Porthogese, P.S. (2000) 5’-Guanidinonaltrindole, a Highly Selective and Potent κ-Opioid Receptor Antagonist. European Journal of Pharmacology, 396, 49-52. http://dx.doi.org/10.1016/S0014-2999(00)00208-9

[103]   Talbot, P.S., Narendran, R., Butelman, E.R., Huang, Y., Ngo, K., Slifstein, M., Martinez, D., Laruelle, M. and Hwang, D.R. (2005) 11C-GR103545, a Radiotracer for Imaging κ Opioid Receptors in Vivo with PET: Synthesis and Evaluation in Baboons. Journal of Nuclear Medicine, 46, 484-494.

[104]   Thomas, J.B., Atkinson, R.N., Rothman, R.B., Fix, S.E., Mascarella, S.W., Vinson, N.A., Xu, H., Dersch, C.M., Lu, Y.F., Cantrell, B.E., Zimmerman, D.M. and Carroll, F.I. (2001) Identifictaion of the First Trans-(3R, 4R)-Dimethyl-4-(3-Hydroxyphenyl) Piperidine Derivative to Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity. Journal of Medicinal Chemistry, 44, 2687-2690. http://dx.doi.org/10.1021/jm015521r

[105]   Thomas, J.B., Atkinson, R.N., Vinson, N.A., Catanzaro, J.L., Peretta, C.L., Fix, S.E., Mascarella, S.W., Rothman, R.B., Xu, H., Dersch, C.M., Lu, Y.F., Cantrell, B.E., Zimmerman, D.M. and Carroll, F.I. (2003) Identification of (3R)-7-Hydroxy-N-((1S)-1-{[(3R, 4R)-4-(3-Hydroxyphenyl)-3,4-Dimethyl-1-Piperidinyl]-2-Methylpropyl-1,2,3,4-Tetrahydro-3-Isoquinolinecarboxamide as a Novel Potent and Selective Opioid κ Receptor Antagonist. Journal of Medicinal Chemistry, 46, 3127-3137.

[106]   Munro, T.A., Berry, L.M., Van’t Veer, A., Beguin, C., Carrol Ivy, F., Zhao, Z., Carlezon, W.A. and Cohen, B.M. (2012) Long-Acting κ Opioid Antagonists Nor-BNI, GNTI and JDTic: Pharmacokinetics in Mice and Lipophilicity. BMC Pharmacology, 12, 5. http://dx.doi.org/10.1186/1471-2210-12-5

[107]   Kim, S.J., Zheng, M.Q., Nabulsi, N., Labarree, D., Ropchan, J., Morris, E.D., Najafzadeh, S., Carson, R.E., Huang, Y. and Morris, E.D. (2013) Determination of the in Vivo Selectivity of a New κ Opioid Receptor Antagonist PET Tracer LY2795050 in the Rhesus Monkey. Journal of Nuclear Medicine, 54, 1668-1674.

[108]   Emson, P.C., Goedert, M., Horsfield, P.M., Riou, F. and St. Pierre, S. (1982) The Regional Distribution and Chromatographic Characterization of Neurotensin-Like Immunoreactivity in the Rat Central Nervous System. Journal of Neurochemistry, 38, 992-999. http://dx.doi.org/10.1111/j.1471-4159.1982.tb05340.x

[109]   Mai, J., Triepel, J. and Metz, J. (1987) Neurotensin in the Human Brain. Neuroscience, 22, 499-524.

[110]   Pelaprat, D. (2006) Interactions between Neurotensin Receptors and G Proteins. Peptides, 27, 2476-2487.

[111]   Alshoukr, F., Prignon, A., Brans, L., Jallane, A., Mendes, S., Talbot, J.N., Tourwe, D., Barbet, J. and Gruaz-Guyon, A. (2011) Novel DOTA-Neurotensin Analogues for 111 In Scintigraphy and 68Ga PET Imaging of Neurotensin Receptor-Positive Tumors. Bioconjugate Chemistry, 22, 1374-1385. http://dx.doi.org/10.1021/bc200078p

[112]   Betancur, C., Canton, M., Burgos, A., Labeeuw, B., Gully, D., Rostene, W. and Pelaprat, D. (1998) Characterization of Binding Sites of a New Neurotensin Receptor Antagonist [3H]SR 142948A, in the Rat Brain. European Journal of Pharmacology, 343, 67-77. http://dx.doi.org/10.1016/S0014-2999(97)01510-0

[113]   Taylor, G.M., Meeran, K., O’Shea, D., Smith, D.M., Ghatei, M.A. and Bloom, S.R. (1996) Adrenomedullin Inhibits Feeding in the Rat by a Mechanism Involving Calcitonin Gene-Related Peptide Receptors. Endocrinology, 137, 3260-3264. http://dx.doi.org/10.1210/endo.137.8.8754748

[114]   Hinson, J.P., Kapasd, S. and Smith, D.M. (2000) Adrenomedullin, a Multifunctional Regulatory Peptide. Endocrine Reviews, 21, 138-167. http://dx.doi.org/10.1210/er.21.2.138

[115]   Privitera, P.J., Beckstead, R.M., Yates, P. and Walgren, R. (2003) Autoradiographic Localization of [125I-Tyr0]Bradykinin Binding Sites in Brains of Wistar-Kyoto and Spontaneously Hypertensive Rats. Cellular and Molecular Neurobiology, 23, 805-815. http://dx.doi.org/10.1023/A:1025061205355

[116]   Lopes, P., Kar, S., Chretien, L., Regoli, D., Quirion, R. and Couture, R. (1995) Quantitative Autoradiographic Localization of [125I-Tyr8] Bradykinin Receptor Binding Sites in the Rat Spinal Cord Effects of Neonatal Capsaicin, Noradrenergic Deafferentiation, Dorsal Rhizotomy and Peripheral Axotomy. Neuroscience, 68, 867-881.

[117]   Saffroy, M., Torrens, Y., Glowinski, J. and Beaujouan, J.C. (2001) Presence of NK2 Binding Sites in the Rat Brain. Journal of Neurochemistry, 79, 985-996. http://dx.doi.org/10.1046/j.1471-4159.2001.00633.x

[118]   Dam, T.V., Escher, E. and Quirion, R. (1990) Visualization of Neurokinin-3 Receptor Sites in Rat Brain Using the Highly Selective Ligand [3H]Senktide. Brain Research, 506, 175-179.

[119]   Buhler, A.V., Proudfit, H.K. and Gebhart, G.F. (2008) Neurotensin-Produced Antinociception in the Rostral Ventromedial Medulla Is Partially Mediated by Spinal Cord Norepinephrine. Pain, 135, 280-290.

[120]   Smith, D.J., Hawranko, A.A., Monroe, P.J., Gully, D., Urban, M.O., Craig, C.R., Smith, J.P. and Smith, D.L. (1997) Dose-Dependent Pain-Facilitatory and -Inhibitory Actions of Neurotensin Are Revealed by SR48692, a Nonpeptide Neurotensin Antagonist: Influence on the Antinociceptive Effect of Morphine. Journal of Pharmacology and Experimental Therapeutics, 282, 899-908.

[121]   Neubert, M.J., Kincaid, W. and Heinricher, M.M. (2004) Nociceptive Facilitating Neurons in the Rostral Ventromedial Medulla. Pain, 110, 158-165.

[122]   Kasckow, J. and Nemeroff, C.B. (1991) The Neurobiology of Neurotensin: Focus on Neurotensin-Dopamine Interactions. Regulatory Peptides, 36, 153-164. http://dx.doi.org/10.1016/0167-0115(91)90053-J

[123]   Mazella, J., Botto, J.M., Guillemare, E., Coppola, T., Sarret, P. and Vincent, J.P. (1996) Structure, Functional Expression, and Cerebral Localization of the Levocabastine-Sensitive Neurotensin/Neuromedin N Receptor from Mouse Brain. Journal of Neuroscience, 16, 5613-5620.

[124]   Schotte, A., Leysen, J.E. and Laduron, P.M. (1986) Evidence for a Displaceable Non Specific [3H]Neurotensin Binding Site in Rat Brain. Naunyn-Schmiedeberg’s Archives of Pharmacology, 333, 400-405.

[125]   St-Gelais, F., Jomphe, C. and Trudeau, L.E. (2006) The Role of Neurotensin in Central Nervous System Pathophysiology: What Is the Evidence? Journal of Psychiatry & Neuroscience, 31, 229-245.

[126]   Hermey, G. (2009) The Vsp10p-Domain Receptor Family. Cellular and Molecular Life Sciences, 66, 2677-2689.

[127]   Mazella, J. (2001) Sortilin/Neurotensin Receptor 3: A New Tool to Investigate Neurotensin Signaling and Cellular Trafficking? Cellular Signalling, 13, 1-6. http://dx.doi.org/10.1016/S0898-6568(00)00130-3

[128]   Petersen, C.M., Nielsen, M.S., Nykjaer, A., Jacobseen, L., Tommerup, N., Rasmussen, H.H., Roigaard, H., Gliemann, J., Madsen, P. and Moestrup, S.K. (1997) Molecular Identification of a Novel Candidate Sorting Receptor Purified from Human Brain by Receptor-associated Protein Affinity Chromatography. Journal of Biological Chemistry, 272, 3599-3605. http://dx.doi.org/10.1074/jbc.272.6.3599

[129]   Martin, S., Vincent, J.P. and Mazella, J. (2003) Involvement of the Neurotensin Receptor-3 in the Neurotensin Iduced Migration of Human Microglia. Journal of Neuroscience, 23, 1198-1205.

[130]   Wu, Z., Martinez-Fong, D., Tredaniel, J. and Forgez, P. (2013) Neurotensin and Its High Affinity Receptor 1 as a Potential Pharmacological Target in Cancer Therapy. Frontiers in Endocrinology, 3, Article 184/1-9.

[131]   Held, C., Plomer, M., Hübner, H., Meltretter, J., Pischetsrieder, M. and Gmeiner, P. (2013) Development of a Metabolically Stable Neurotensin Receptor 2 (NTS2) Ligand. ChemMedChem, 8, 75-81.

[132]   Held, C., Hübner, H., Kling, R., Nagel, Y.A., Wennemers, H. and Gmeiner, P. (2013) Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor2 (NTS2)-Selective Peptide-Peptoid Hybrids. ChemMed Chem., 8, 772-778.

[133]   Maschauer, S., Einsiedel, J., Hocke, C., Hübner, H., Kuwert, T., Gmeiner, P. and Prante, O. (2010) Synthesis of a 68Ga-Labeled Peptoid-Peptide Hybrid for Imaging of Neurotensin Receptor Expression in Vivo. ACS Medicinal Chemistry Letters, 1, 224-228.http://dx.doi.org/10.1021/ml1000728

[134]   Maschauer, S., Ruckdeschl, T., Tripal, P., Haubner, R., Einsiedel, J., Hübner, H., Gmeiner, P., Kuwert, T. and Prante, O. (2014) In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study. Pharmaceuticals, 7, 464-481.

[135]   Gully, D., Canton, M., Boigegrain, R., Jeanjean, F., Molimard, J.C., Poncelet, M., Gueudet, C., Heaulme, M., Leyris, R., Brouard, A., Pelaprat, D., Labbe-Jullie, C., Mazella, J., Soubrie, P., Maffrand, J.P., Rostene, W., Kitabgi, P. and Le Fur, G. (1993) Biochemical and Pharmacological Profile of a Potent and Selective Nonpeptide Antagonist of the Neurotensin Receptor. Proceedings of the National Academy of Sciences of the United States of America, 90, 65-69.

[136]   Gully, D., Labeeuw, B., Boigegrain, R., Oury-Donat, F., Bachy, A., Poncelet, M., Steinberg, R., Suaud-Chagny, M.F., Santucci, V., Vita, N., Pecceu, F., Labbe-Jullie, C., Kitabgi, P., Soubrie, P., Le Fur, G. and Maffrand, J.P. (1997) Biochemical and Pharmacological Activities of SR 142948A, a New Potent Neurotensin Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 280, 802-812.

[137]   Luo, G., Chen, L., Civiello, R., Pin, S.S., Xu, C., Kostich, W., Kelley, M., Conway, C.M., Macor, J.E. and Dubowchik, G.M. (2012) Calcitonin Gene-Related Peptide Receptor Antagonist. Bioorganic & Medicinal Chemistry Letters, 22, 2917-2921. http://dx.doi.org/10.1016/j.bmcl.2012.02.065

[138]   Durham, P.L. (2008) Inhibition of Calcitonin Gene-Related Peptide Function: Promisingstrategy for Treating Migraine. Headache, 48, 1269-1275. http://dx.doi.org/10.1111/j.1526-4610.2008.01215.x

[139]   Ho, T.W., Edvinsson, L. and Goadsby, P.J. (2010) CGRP and Its Receptor Provide New Insights into Migraine Pathophysiology. Nature Reviews Neurology, 6, 573-582.

[140]   Eftekhari, S. and Edvinsson, L. (2010) Possible Sites of Action of the New Calcitonin Gene-Related Peptide Receptor Antagonist. Therapeutic Advances in Neurological Disorders, 3, 369-378.

[141]   Edvinsson, L., Mc Culloch, J., Kingman T. and Uddman, R. (1986) On the Functional Role of Trigemino-Cerebral Circulation. In: Owman, C. and Hardebo, J.E., Eds., Neural Regulation of Cerebral Circulation of the Cerebral Circulation, Elsevier Science, Amsterdam, 407-418.

[142]   Markowitz, S., Saito, K. and Moskowitz, M.A. (1987) Neurogenically Mediated Leakage of Plasma Protein Occurs from Blood Vessels in Dura Mater but Not Brain. Journal of Neuroscience, 7, 4129-4136.

[143]   Moore, E.I. and Salvatore, C.A. (2012) Targeting a Family B GPCR/RAMP Receptor Complex: CGRP Receptor Antagonists and Migraine. British Journal of Pharmacology, 166, 66-78.

[144]   Mc Latchie, L.M., Fraser, N.J., Main, M.J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M.G. and Ford, S.M. (1998) RAMPs Regulate the Transport and Ligand Specifity of the Calcitonin-Receptor-Like Receptor. Nature, 393, 333-339. http://dx.doi.org/10.1038/30666

[145]   Buhlmann, N., Leuthauser, K., Muff, R., Fischer, J. and Bonn, W. (1999) A Receptor Activity Protein RAMP2-Dependent Adrenomedullin Receptor Is a Calcitonin Gene-Related Peptide Receptor When Coexpressed with Human RAMP1. Endocrinology, 140, 2883-2890.

[146]   Evans, C.J., Keith, D.E., Morrison, H., Magendzo, K. and Edwards, R.H. (1992) Cloning of a Delta Opioid Receptor by Functional Expression. Science, 258, 1952-1955. http://dx.doi.org/10.1126/science.1335167

[147]   Alexander, S., Mathie, A. and Peters, J.A. (2011) Guide to Receptors and Channels (GRAC), 5th Edition. British Journal of Pharmacology, 164, S1-S324.

[148]   Hay, D.L. and Dickerson, I.M. (2010) The Calcitonin Gene-Related Peptide Family. Springer Science and Business Media B.V., Dodrecht, Heidelberg, London.

[149]   Edvinsson, L., Villalon, C.M. and MaasssenVanDenBrink, A. (2012) Basic Mechanisms of Migraine and Its Acute Treatment. Pharmacology & Therapeutics, 136, 319-333.

[150]   Rudolf, K., Eberlein, W., Engel, W., Pieper, H., Entzeroth, M., Hallermayer, G. and Doods, H. (2005) Development of Human Calcitonin Gene-Related Peptide (CGRP) ReceptorAntagonists. 1. Potent and Selective Small Molecule CGRP Angonists. 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-Llysyl]-4-(4-pyridinyl)piperazine: The First CGRP Antagonist for Clinical Trials in Acute Migraine. Journal of Medicinal Chemistry, 48, 5921-5931.

[151]   Quayle, J.M., Bonev, A.D., Brayden, J.E. and Nelson, M.T. (1994) Calcitonin Gene Related Peptide Activated ATP Sensitive K+ Currents in Rabbit Arterial Smooth Muscle via Protein Kinase A. Journal of Physiology, 475, 9-13.

[152]   Blankeney, J.S., Reid, R.C., Le, G.T. and Fairlie, D.P. (2007) Nonpeptide Ligands for Peptide Activated G-ProteinCoupled Receptors. Chemical Reviews, 107, 2960-3041. http://dx.doi.org/10.1021/cr050984g

[153]   Hostetler, E.D., Joshi, A.D., Sanabria-Bohorquez, S., Fan, H., Zeng, Z., Purcell, M., Gantert, L., Riffel, K., William, M., O’Malley, S., Miller, P., Selnick, H.G., Gallicchio, S.N., Bell, I.M., Salvatore, C., Kane, S.A., Li, C.C., Hargreaves, R., de Groot, T., Bormans, G., van Hecken, A., Derdelinckx, I., de Hoon, J., Reynders, T., Declercq, R., de Lepeleire, I., Kennedy, W.D., Blanchard, R., Marcantonio, E.E., Sur, C., Cook, J.J., van Laere, K. and Evelhoch, J.L. (2013) In Vivo Quantification of Calcitonin Gene Related Peptide (CGRP) Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography (PET)Tracer [11C]MK-4232. Journal Of Pharmacology and Experimental Therapeutics, 347, 478-486. http://dx.doi.org/10.1124/jpet.113.206458

[154]   Mallee, J.J., Salvatore, C.A., LeBourdelles, B., Oliver, K.R., Longmore, J., Koblan, K.S. and Kane, S.A. (2002) Receptor Activity-Modyfying Protein I Determines the Species Selectivity of Nonpeptide CGRP Receptor Antagonists. Journal of Biological Chemistry, 277, 14294-14298.

[155]   Weiller, C., May, A., Limmroth, V., Jüptner, M., Kaube, H., Schayck, R.V., Coenen, H.H. and Diener, H.C. (1995) Brain Stem Activation in Spontaneous Human Migraine Attacks. Nature Medicine, 1, 658-660.

[156]   Olesen, J., Diener, H.C., Husstedt, I.W., Goadsby, P.J., Hall, D., Meier, U., Pollentier, S. and Lesko, L.M. (2004) Calcitonin Gene-Related Peptide Receptor Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. New England Journal of Medicine, 350, 1104-1110. http://dx.doi.org/10.1056/NEJMoa030505

[157]   Diener, H.C., Barbanti, P., Dahlof, C., Reuter, U., Habeck, J. and Podhorna, J. (2010) BI 44370 TA, an Oral CGRP Antagonist for the Treatment of Acute Migraine Attacks: Results from a Phase II Study. Cephalalgia, 31, 573-584.

[158]   Degnan, A.P., Chaturvedula, P.V., Conway, C.M., Cook, D.A., Davis, C.D., Denton, R., Han, X., Macci, R., Mathias, N.R., Moench, P., Pin, S.S., Ren, S.X., Schartman, R., Signor, L.J., Thalody, G., Widman, K.A., Xu, C., Macor, J.E. and Dubowchik, G.M. (2008) Discovery of R-4-(8-Fluoro-2-Oxo-1,2-Dihydro-Quinazolin-3 (4H)-yl)-N(3-(7-Methyl1H-indazol-5-yl)propan-2yl) Piperidin-1-Carboxamide (BMS-694153): A Potent Antagonist of the Human Calcitonin Gene Related Peptide Receptor for Migraine with Rapid and Efficient Intranasal Exposure. Journal of Medicinal Chemistry, 51, 4858-4861.

[159]   Bell, I.M., Gallichio, S.N., Wood, M.R., Quigley, A.G., Stump, C.A., Zartman, C.B., Fay, J.F., Li, C.C., Lynch, J.J., Moore, E.L., Mosser, S.D., Prueksaritanont, T., Regan, C.P., Roller, S., Salvatore, C.A., Kane, S.A., Vacca, J.P. and Selnick, H.G. (2010) Discovery of MK-3207: A Highly Potent Orally Available CGRP Receptor Antagonist. ACS Medicinal Chemistry Letters, 1, 24-29. http://dx.doi.org/10.1021/ml900016y

[160]   Bell, I.M., Stump, C.A., Gallichio, S.N., Staas, D.D., Zartmann, C.B., Moore, E.L., Sain, N., Urban, M., Bruno, J.G., Calamari, A., Kemmerer, A.L., Mosser, E.L., Fandozzi, C., White, R.B., Zrada, M.M., Selnick, H.G., Graham, S.L., Vacca, J.P., Kane, S.A. and Salvatore, C.A. (2012) MK-8825: Apotent and Selective CGRP Receptore Antagonist with Good Oral Activity in Rats. Bioorganic & Medicinal Chemistry Letters, 22, 3941-3945.

[161]   Trabold, R., Eros, C., Zweckenberger, K., Relton, J., Beck, H., Nussberger, J., Müller-Esterl, W., Bader, M., Whalley, E. and Plesnila, N. (2010) The Role of Bradykinin B1 and B2 Receptors for Secondary Brain Damage after Traumatic Brain Injury in Mice. Journal of Cerebral Blood Flow & Metabolism, 30, 130-139.

[162]   Moreau, M.E., Garbacki, N., Molinaro, G., Brown, N.J., Marceau, F. and Adam, A. (2005) The Kallikrein-Kinin System: Current and Future Pharmacological Targets. Journal of Pharmacological Sciences, 99, 6-38.

[163]   Nussberger, J., Cugno, M., Amstutz, C., Cicardi, M., Pellacani, A. and Agostoni, A. (1998) Plasma Bradykinin in Angio-Oedema. Lancet, 351, 1693-1697. http://dx.doi.org/10.1016/S0140-6736(97)09137-X

[164]   Camarda, V., Rizzi, A., Calo, G., Wirth, K. and Regoli, D. (2002) Pharmacological Characterization of Novel B2 Receptor Ligands. Canadian Journal of Physiology and Pharmacology, 80, 281-286. http://dx.doi.org/10.1139/y02-037

[165]   Campos, M.M., Leal, P.C., Yunes, R.A. and Cakixto, J.B. (2006) Non-Peptide Antagonists for Kinin B1 Receptors: New Insights into Their Therapeutic Potential for the Management of Inflammation and Pain. Trends in Pharmacological Sciences, 27, 646-651. http://dx.doi.org/10.1016/j.tips.2006.10.007

[166]   Raidoo, D.M. and Bhoola, K.D. (1997) Kinin Receptors on Human Neurones. Journal of Neuroimmunology, 77, 39-44.

[167]   Cholewinski, A.J., Stevens, G., Mc Dermott, A.M. and Wilkin, G.P. (1991) Identification of B2 Bradykinin Binding Sites on Cutured Cortical Astrocytes. Journal of Neurochemistry, 57, 1456-1458.

[168]   Noda, M., Kariura, Y., Amano, T., Manago, Y., Nishikawa, K., Aoki, S. and Wada, K. (2003) Expression and Function of Bradykinin Receptors in Microglia. Life Sciences, 72, 1573-1581

[169]   Murone, C., Paxinos, G., McKinley, M.J., Oldfield, B.J., Müller-Esterl, W., Mendelsohn, F.A.O. and Chai, S.Y. (1997) Distribution of Bradykinin B2 Receptors in Sheep Brain and Spinal Cord Visualized by in Vitro Autoradiography. Journal of Comparative Neurology, 381, 203-218.

[170]   Wahl, M., Young, A.R., Edvinsson, L. and Wagner, F. (1983) Effects of Bradykinin on Pial Arteries and Arterioles in Vitro and in Situ. Journal of Cerebral Blood Flow & Metabolism, 3, 231-237. http://dx.doi.org/10.1038/jcbfm.1983.31

[171]   Whalley, E.T. and Wahl, M. (1983) Analysis of Bradykinin Receptor Mediating Relaxation of Cat Cerebral Arteries in Vivo and in Vitro. Naunyn-Schmiedeberg’s Archives of Pharmacology, 323, 66-71.

[172]   Regoli, D., Allogho, S.N., Rizzi, A. and Gobeil, F.J. (1998) Bradykinin Receptors and Their Antagonists. European Journal of Pharmacology, 348, 1-10. http://dx.doi.org/10.1016/S0014-2999(98)00165-4

[173]   Cole, S.W. and Lundquist, L.M. (2013) Icatibant for the Treatment of Hereditary Angioedema. Annals of Pharmacotherapy, 47, 49-55. http://dx.doi.org/10.1345/aph.1R423

[174]   Lumry, W.R., Li, H.H., Levy, R.J., Potter, P.C., Farkas, H., Moldovan, D., Riedl, M., Craig, T., Bloom, B.J. and Reshef, A. (2011) Randomized Placebo-Controlled Trial of the Bradykinin B2 Receptor Antagonist Icatibant for the Treatment of Acute Attacks of Hereditary Angioedema: FAST-3 Trial. Annals of Allergy, Asthma & Immunology, 107, 529-537.

[175]   Aramori, I., Zenkoh, J., Morikawa, N., O’Donnell, N., Asano, M., Nakamura, K., Iwami, M., Kojo, H. and Notsu, Y. (1997) Novel Subtype-Selective Nonpeptide Bradykinin Receptor Antagonists FR167344 and FR 173657. Molecular Pharmacology, 51, 171-176.

[176]   Pruneau, D., Paquet, J.L., Luccarini, J.M., Defrene, E., Fouchet, C., Franck, R.M., Loillier, B., Robert, C., Belichard, P., Duclos, H., Cremers, B. and Dodey, P. (1999) Pharmacological Profile of LF 16-0687, a New Potent Non-Peptide Bradykinin B2 Receptor Antagonist. Immunopharmacology, 43, 187-194.

[177]   Asano, M., Inamura, N., Hatori, C., Sawai, H., Fujiwara, T., Katayama, A., Kayakiri, H., Satoh, S., Abe, Y., Inoue, T., Sawada, Y., Nakahara, K., Oku, T. and Okuhara, M. (1997) The Identification of an Orally Active, Nonpeptide Bradykinin B2 Receptor Antagonist, FR173657. British Journal of Pharmacology, 120, 617-624.

[178]   Giardina, G.A.M. and Raveglia, L.F. (1997) Neurokinin-3 Receptor Antagonists. Expert Opinion on Therapeutic Patents, 7, 307-323. http://dx.doi.org/10.1517/13543776.7.4.307

[179]   Page, N.M. (2006) Characterization of the Gene Structures, Precursor Processing and Pharmacology of the Endokinin Peptides. Vascular Pharmacology, 45, 200-208.

[180]   Pennefather, J.N., Lecci, A., Candenas, M.L., Patak, E., Pinto, F.M. and Maggi, C.A. (2004) Tachykinins and Tachykinin Receptors: A Growing Family. Life Sciences, 74, 1445-1463. http://dx.doi.org/10.1016/j.lfs.2003.09.039

[181]   Helke, C.J., Krause, J.E., Mantyh, P.W., Couture, R. and Bannon, M.J. (1990) Diversity in Mammalian Tachykinin Peptidergic Neurons: Multiple Peptides, Receptors and Regulatory Mechanisms. FASEB Journal, 4, 1606-1615.

[182]   Nussdorfer, G.G. and Malendowicz, L.K. (1998) Role of Tachykinins in the Regulation of the Hypothalamo-PituitaryAdrenal Axis. Peptides, 19, 949-968. http://dx.doi.org/10.1016/S0196-9781(98)00017-5

[183]   Wang, Y., Barton, B., Nielsen, P.F. and Conlon, J.M. (1999) Tachykinins (Substance P and Neuropeptide γ) from the Brains of the Pallid Sturgeon, Scaphirhynchus Albus and the Paddelfish, Polyodon Spathula (Acipenseriformes). General and Comparative Endocrinology, 116, 21-30. http://dx.doi.org/10.1006/gcen.1999.7348

[184]   Morteau, O., Lu, B., Gerard, C. and Gerard, N.P. (2001) Hemokinin Is a Full Agonist at the Substance P Receptor. Nature Immunology, 2, 1088. http://dx.doi.org/10.1038/ni1201-1088

[185]   Jones, S., Tucker, K.L., Sage, T., Kaiser, W.J., Barrett, N.E., Lowry, P.J., Zimmer, A., Hunt, S.P., Emerson, M. and Gibbins, J.M. (2008) Peripheral Tachykinins and the Neurokinin Receptor NK1 Are Required for Platelet Thrombus Formation. Blood, 111,605-612. http://dx.doi.org/10.1182/blood-2007-07-103424

[186]   Nowicki, M., Ostalska-Nowicka, B., Kondraciuk, B. and Miskowiak, B. (2007) The Significance of Substance P in Physiological and Malignant Haematopoesis. Journal of Clinical Pathology, 60, 749-755.

[187]   Page, N.M., Bell, N.J., Gardiner, S.M., Manyonda, I.T., Brayley, K.J., Strange, P.G. and Lowry, P.J. (2003) Characterization of the Endokinins: Human Tachykinins with Cardiovascular Activity. Proceedings of the National Academy of Sciences of the United States of America, 100, 6245-6250. http://dx.doi.org/10.1073/pnas.0931458100

[188]   Kurtz, M.M., Wang, R., Clements, M.K., Cascieri, M.A., Austin, C.P., Cunningham, B.R., Chicci, G.G. and Liu, Q.Y. (2002) Identification, Localization and Receptor Characterization of Novel Mammalian Substance p-Like Peptides. Gene, 296, 205-212. http://dx.doi.org/10.1016/S0378-1119(02)00861-2

[189]   Debeljuk, L. and Lasaga, M. (1999) Modulation of the Hypothalamo-Pituitary-Gonadal Axis and the Pineal Gland by Neurokinin A, Neuropeptide K and Neuropeptide γ. Peptides, 20, 285-299.

[190]   Loesch, A., Domer, F.R., Alexander, B. and Burnstock, G. (1993) Electron-Immunocytochemistry of Peptides in Endothelial Cells of Rabbit Cerebral Vessels Following Perfusion with a Perfluorocarbon Emulsion. Brain Research, 611, 333-337. http://dx.doi.org/10.1016/0006-8993(93)90522-O

[191]   Metwali, A., Blum, A.M., Ferraris, L., Klein, J.S., Fiocchi, C. and Weinstock, J.V. (1994) Eosinophils within the Healthy or Inflamed Human Intestine Produce Substance P and Vasoactive Intestinal Peptide. Journal of Neuroimmunology, 52, 69-78. http://dx.doi.org/10.1016/0165-5728(94)90164-3

[192]   Khawaja, A.M. and Rogers, D.F. (1996) Tachykinins: Receptor to Effector. International Journal of Biochemistry & Cell Biology, 28, 721-738. http://dx.doi.org/10.1016/1357-2725(96)00017-9

[193]   Beaujouan, J.C., Torrens, Y., Saffroy, M. and Glowinski, J. (1986) Quantitative Autoradiographic Analysis of the Distribution of Binding Sites for [125I]-Bolton-Hunter Derivatives of Eledoisin and Substance P in the Rat Brain. Neuroscience, 18, 857-875. http://dx.doi.org/10.1016/0306-4522(86)90105-3

[194]   Page, N.M. (2005) New Challenges in the Study of the Mammalian Tachykinins. Peptides, 26, 1356-1368.

[195]   Zhang, Y., Lu, L., Furlonger, C., Wu, G.E. and Paige, C.J. (2000) Hemokinin Is a Hematopoetic-Specific Tachykinin that Regulates B Lymphopoiesis. Nature Immunology, 1, 392-397.

[196]   DeFea, K.A., Vaughan, Z.D., O’Bryan, E.M., Nishijima, D., Dery, O. and Bunnett, N.W. (2000) The Proliferative and Antiapoptotic Effects of Substance P Are Facilitated by Formation of a β-Arrestin-Dependent Scaffolding Complex. Proceedings of the National Academy of Sciences of the United States of America, 97, 11086-11091.

[197]   Regoli, D., Drapeau, G., Dion, S. and D’Orleans-Juste, P. (1987) Pharmacological Receptors for Substance P and Neurokinins. Life Sciences, 40, 109-117. http://dx.doi.org/10.1016/0024-3205(87)90349-3

[198]   DeFelipe, C., Herrero, J.F., O’Brien, J.A., Palmer, J.A., Doyle, C.A., Smith, A.J.H., Laird, J.M.A., Belmonte, C., Cervero, F. and Hunt, S.P. (1998) Altered Nociception, Analgesia and Aggression in Mice Lacking the Receptor for Substance P. Nature, 392, 394-397. http://dx.doi.org/10.1038/32904

[199]   Leroy, V., Mauser, P., Gao, Z.L. and Peet, N.P. (2000) Neurokinin Receptor Antagonists. Expert Opinion on Investigational Drugs, 9,735-746. http://dx.doi.org/10.1517/13543784.9.4.735

[200]   Belzung, C. (2014) Innovative Drugs to Treat Depression: Did Animal Models Fail to Be Predictive or did Clinical Trials Fail to Detect Effects. Neuropsychopharmacology, 39, 1041-1051.

[201]   McCarson, K.E. and Krause, J.E. (1994) NK-1 and NK-3 Type Tachykinin Receptor mRNA Expression in the Rat Spinal Cord Dorsal Horn Is Increased during Adjuvant or Formalin-Induced Nociception. Journal of Neuroscience, 14, 712-720.

[202]   Inquimbert, P. and Scholz, J. (2012) In: Brady, S.T., Siegel, G.J., Albers, R.W., Price, D.L., Benjamins, J., Fisher, S., Hall, A., Bazan, N., Coyle, J. and Sisodia, S., Eds., Pain: Basic Neurochemistry, Principles of Molecular, Cellular and Medical Neurobiology, Academic Press-Elsevier, Waltham, Oxford, 928-941.

[203]   Yashpal, K., Dam, T.V. and Quirion, R. (1990) Quantitative Autoradiographic Distribution of Multiple Neurokinin Binding Sites in Rat Spinal Cord. Brain Research, 506, 259-266.

[204]   Greenspan, R.L., Suprenant, V. and Atem, F. (2012) Visualization of Distal Spinal Cord on F-18 FDG PET/CT. Clinical Nuclear Medicine, 37, 137-141. http://dx.doi.org/10.1097/RLU.0b013e31823933a4

[205]   Floeth, F.W., Galldiks, N., Eicker, S., Stoffels, G., Herdmann, J., Steiger, H.J., Antoch, G., Rhee, S. and Langen, K.J. (2013) Hypermetabolism in 18F-FDG PET Predicts Favorable Outcome Following Decompressive Surgery in Patients with Degenerative cervical Myelopathy. Journal of Nuclear Medicine, 54, 1577-1583.

[206]   Wu, C., Zhu, J., Baeslack, J., Zaremba, A., Hecker, J., Kraso, J., Matthews, P.M., Miller, R.H. and Wang, Y.M. (2013) Longitudinal Positron Emission Tomography Imaging for Monitoring Myelin Repair in the Spinal Cord. Annals of Neurology, 74, 688-698. http://dx.doi.org/10.1002/ana.23965

[207]   De Paula Faria, D., Copray, S., Sijbesma, J.W.A., Willemsen, A.T.M., Buchpiguel, C.A., Dierchx, R.A.J.O. and deVries, E.F.J. (2014) PET Imaging of Focal Demyelination and Remyelination in a Rat Model of Multiple Sclerosis: Comparison of [11C]MeDAS, [11C]CIC and [11C]PIB. European Journal of Nuclear Medicine and Molecular Imaging, 41, 995-1003. http://dx.doi.org/10.1007/s00259-013-2682-6

[208]   Langlois, X., Wintmolders, C., Te Riele, P., Leyen, J.B. and Jurzak, M. (2001) Detailed Distribution of Neurokinin 3 Receptors in the Rat, Guinea-Pig and Gerbil Brain: A Comparative Autoradiographic Study. Neuropharmacology, 40, 242-253. http://dx.doi.org/10.1016/S0028-3908(00)00149-0

[209]   Almeida, T.A., Rojo, J., Nieto, P.M., Hernandez, M., Martin, J.D. and Candenas, M.L. (2004) Tachykinin and Tachykinin Receptors: Structure and Activity Relationships. Current Medicinal Chemistry, 11, 2045-2081.

[210]   Rigby, M., O’Donnell, R. and Rupniak, N.M. (2005) Species Differences in Tachykinin Receptor Distribution: Further Evidence that the Substance P (NK1) Receptor Predominates in Human Brain. Journal of Comparative Neurology, 490, 335-353. http://dx.doi.org/10.1002/cne.20664

[211]   Quartara, L., Altamura, M., Evangelista, S. and Maggi, C.A. (2009) Tachykinin Receptor Antagonists in Clinical Trials. Expert Opinion on Investigational Drugs, 18, 1843-1864.

[212]   Wolfensberger, S.P.A., van Berckel, B.N.M., Airaksinen, A.J., Maruyama, K., Lubberink, M., Boellard, R., Carey, W.D.H., Reddingius, W., Veltman, D.J., Windhorst, A.D., Leysen, J.E. and Lammertsma, A.A. (2009) First Evaluation of [11C]R116301 as an in Vivo Tracer of NK1 Receptors in Man. Molecular Imaging and Biology, 11, 241-245.

[213]   Snider, R.M., Constantine, J.W., Lowe, I.J., Longo, K.P., Lebel, W.S., Woody, H.A., Orozda, S.E., Oesai, M.C., Vinick, F.J., Spencer, R.W. and Hess, H.J. (1991) A Potent Non Peptide Antagonist of the Substance P (NK1) Receptor. Science, 251, 435-437. http://dx.doi.org/10.1126/science.1703323

[214]   Dionne, R.A., Max, M.B., Gordon, S.M., Parada, S., Sang, C., Gracely, R.H., Sethna, N.F. and MacLean, D.B. (1998) The Substance P Receptor Antagonist CP-99,994 Reduces Acute Postoperative Pain. Clinical Pharmacology & Therapeutics, 64, 562-568. http://dx.doi.org/10.1016/S0009-9236(98)90140-0

[215]   Gardner, C.J., Armour, D.R., Beattie, D.T., Gale, J.D., Hawcock, A.B., Kilpatrick, G.J., Twissell, D.J. and Ward, P. (1996) GR205171: A Novel Antagonist with High Affinity for the Tachykinin NK1 Receptor, and Potent Broad Spectrum Antiemetic Activity. Regulatory Peptides, 65, 45-53.

[216]   Zamuner, S., Rabiner, E.A., Fernandes, S.A., Bani, M., Gunn, R.N., Gomeni, R., Ratti, E. and Cunningham, V.J. (2012) A Pharmacokinetic PET Study of NK1 Receptor Occupancy. European Journal of Nuclear Medicine and Molecular Imaging, 39, 226-235. http://dx.doi.org/10.1007/s00259-011-1954-2

[217]   Kramer, M.S., Cutler, N., Feighner, J., Shrivastava, R., Carman, J., Sramek, J.J., Reines, S.A., Liu, G., Snavely, D., Wyatt-Knowles, E., HaIe, J.J., Mills, S.G., MacCoss, M., Swain, C.J., Harrison, T., Hili, R.G., Hefti, F., Scolnick, E.M., Cascieri, M.A., Chicchi, G.G., Sadowski, S.H., Williams, A.R., Hewson, L., Smith, D., Carlson, E.J., Hargreaves, R.J. and Rupniak, N.M.J. (1998) Distinct Mechanisms for Antidepressant Activity by Blockade of Central Substance P Receptors. Science, 281, 1640-1645. http://dx.doi.org/10.1126/science.281.5383.1640

[218]   Rupniak, N.M. and Kramer, M.S. (1999) Discovery of the Antidepressant and Anti-Emetic Efficacy of Substance P Receptor (NK1) Antagonists. Trends in Pharmacological Sciences, 20, 485-490.

[219]   Tatersall, F.D., Rycroft, W., Cumberbatch, M., Mason, G., Tye, S., Ber, E., Cascieri, M., Hill, R.G., MacIntyre, D.E. and Hargreaves, R.J. (2000) The Novel NK1 Receptor Antagonist MK-0869 (L-754,030) and Its Water Soluble Phosphoryl Prodrug, L-758,298, Inhibit Acute and Delayed Cisplatin-Induced Emesis in Ferrets. Neuropharmacology, 39, 652-663. http://dx.doi.org/10.1016/S0028-3908(99)00172-0

[220]   Bergstrom, M., Hargreaves, R.J., Burnes, H.D., Goldberg, M.R., Sciberras, D., Reines, S.A., Petty, K.J., Ogren, M., Antoni, G., Langstrom, B., Eskola, O., Scheinin, M., Solin, O., Majumdar, A.K., Constanzer, M.L., Battisti, W.P., Bradstreet, T.E., Gargano, C. and Hietala, J. (2004) Human Positron Emission Tomography Studies of Brain Neurokinin 1 Receptor Occupancy by Aprepitant. Biological Psychiatry, 55, 1007-1012.

[221]   Solin, O., Eskola, O., Hamill, T.G., Bergmann, J., Lehikoinen, P., Gronroos, T., Forsback, S., Haaparanta, M., Viljanen, T., Ryan, C., Gibson, R., Kieczykowski, G., Hietala, J., Harsgreaves, R. and Burns, H.D. (2004) Synthesis and Characterization of a Potent, Selective, Radiolabelled Substance P Antagonist for NK1 Receptor Quantification: ([18F]SPA-RQ). Molecular Imaging & Biology, 6, 373-384. http://dx.doi.org/10.1016/j.mibio.2004.08.001

[222]   Keller, M., Montgomery, S., Ball, W., Morrison, M., Snavely, D., Liu, G., Hargreaves, R., Hietala, J., Lines, C., Beebe, K. and Reines, S. (2006) Lack of Efficacy of the Substance P (Neurokinin1 Receptor) Antagonist Aprepitant in the Treatment of Major Depressive Disorder. Biological Psychiatry, 59, 216-223.

[223]   Fujimura, Y., Yasuno, F., Farris, A., Liow, J.S., Geraci, M., Drevets, W., Pine, D.S., Ghose, S., Lerner, A., Hargreaves, R., Burns, H.D., Morse, C., Pike, V.W. and Innis, R.B. (2009) Decreased Neurokinin-1 (Substance P) Receptor Binding in Patients with Panic Disorder: Positron Emission Tomographic Study with [18F]SPA-RQ. Biological Psychiatry, 66, 94-97. http://dx.doi.org/10.1016/j.biopsych.2008.12.027

[224]   Dorn, C.P., Hale, J.J., MacCoss, M., Mills, S.G., Ladduwahetty, T. and Shah, S.K. (1994) Morpholine and Thiomorpholine Tachikinin Receptor Antagonists. European Patent Application EP 577394 B1.

[225]   Dorn, C.P., Hale, J.J., MacCoss, M. and Mills, S.G. (1995) Preparation of Morpholine Tachykinin Receptor Antagonist Prodrugs. PCT Int. Appl.,WO9523798 A1 19950908

[226]   Dorn, C.P., Finke, P.E., Hale, J.J., MacCoss, M., Mills, S.G., Shrenik, K., Chambers, M.S., Harrison, T., Ladduwahetty, T. and Williams, B.J. (1995) Morpholine and Thiomorpholine Tachikinin Receptor Antagonists. International Application (Patent Cooperation Treaty), WO 9516679 A1.

[227]   Megens, A.A., Ashton, D., Vermeire, J.C., Vermote, P.C., Hens, K.A., Hillen, L.C., Fransen, J.F., Mahieu, M., Heylen, L., Leysen, J.E., Jurzak, M.R. and Janssens, F. (2002) Pharmacological Profile of (2R-trans)-4-[1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate(R116301), an Orally and Centrally Active Neurokinin-1 Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 302, 696-709. http://dx.doi.org/10.1124/jpet.102.034348

[228]   Van der Mey, M., Janssens, C.G.M., Janssens, F.E., Jurzak, M., Langois, X., Sommen, F.M., Verreet, B., Windhorst, A.D., Leysen, J.E. and Herscheid, J.D.M. (2005) Synthesis and Biodistribution of [11C]R116301, a Promising PET Ligand for Central NK1 Receptors. Bioorganic & Medicinal Chemistry, 13, 1579-1586.

[229]   Bender, D., Olsen, A.K., Marthi, M.K., Smith, D.F. and Cumming, P. (2004) PET Evaluation of the Uptake of N-[11C]methyl CP-643,051, an NK1 Receptor Antagonist, in the Living Porcine Brain. Nuclear Medicine and Biology, 31, 699-704. http://dx.doi.org/10.1016/j.nucmedbio.2004.03.005

[230]   Shimizu, Y., Matsuyama, H., Shiina, T., Takewaki, T. and Furness, J.B. (2008) Tachykinin and Their Functions in the Gastrointestinal Tract. Cellular and Molecular Life Sciences, 65, 295-311.

[231]   Bensaid, M., Faucheux, B.A., Hirsch, E., Agid, Y., Soubrié, P. and Oury-Donat, F. (2001) Expression of Tachykinin NK2 Receptor mRNA in Human Brain. Neuroscience Letters, 303, 25-28.

[232]   Chin, F.T., Morse, C.L., Shetty, H.U. and Pike, V.W. (2006) Automated Radiosynthesis of [18F]SPA-RQ for Imaging Human Brain NK1 Receptors with PET. Journal of Labelled Compounds and Radiopharmaceuticals, 49, 17-31.

[233]   Emonds-Alt, X., Vilain, P., Proietto, V., van Broeck, D., Advenier, C., Naline, E., Neliat, G., Le Fur, G. and Breliere, J.C. (1992) A Potent and Selective Non-Peptide Antagonist of the Neurokinin (NK2) Receptor. Life Sciences, 50, PL101-PL106.

[234]   Catalioto, R.M., Criscuoli, M., Cucchi, P., Giachetti, A., Giannoti, D., Giuliani, A., Lecci, A., Lippi, A., Patarcchini, R., Quartara, L., Renzetti, A.R., Tramontana, M., Arcamone, F. and Maggi, C.A. (1998) MEN 11420 (Nepadutant), a Novel Glycosylated Bicyclic Peptide Tachykinin NK2 Receptor Antagonist. British Journal of Pharmacology, 123, 81-91. http://dx.doi.org/10.1038/sj.bjp.0701587

[235]   Bai, T.R., Zhou, D., Weir, T., Walker, B., Hegele, R., Hayashi, S., McKay, K., Bondy, G.P. and Fong, T. (1995) Substance P (NK1)-and Neurokinin A (NK2)-Receptor Gene Expression in Inflammatory Airway Disease. American Journal of Physiology, 269, L309-L317.

[236]   Louis, C., Stemmelin, J., Boulay, D., Bergis, O., Cohen, C. and Griebel, G. (2008) Additional Evidence for Anxiolyticand Antidepressant-Like Activities of Saredutant (SR48968), an Antagonist at the Neurokinin-2 Receptor in Various Rodent-Models. Pharmacology Biochemistry and Behavior, 89, 36-45. http://dx.doi.org/10.1016/j.pbb.2007.10.020

[237]   Emonds-Alt, X., Bichon, D., Ducoux, J.P., Heaulme, M., Miloux, B., Poncelet, M., Proietto, V., Van Broeck, D., Vilain, P., Neliat, G., Soubrie, P., Le Fur, G. and Breliere, J.C. (1995) SR 142801, the First Potent Non-Peptide Antagonist of the Tachykinin NK3 Receptor. Life Sciences, 56, PL27-PL32.

[238]   Sarau, H.M., Griswold, D.E., Potts, W., Foley, J.J., Schmidt, D.B., Webb, E.F., Martin, L.D., Brawner, M.E., Elshourbagy, N.A., Medhurst, A.D., Giardina, G.A. and Hay, D.W. (1997) Nonpeptide Tachykinin Receptor Antagonists: I. Pharmacological and Pharmacokinetic Characterization of SB 223412, a Novel, Potent and Selective Neurokinin-3 Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 281, 1303-1311.

[239]   Natsugari, H., Ikeura, Y., Kamo, I., Ishimaru, T., Ishichi, Y., Fujishima, A., Tanaka, T., Kasahara, F., Kawada, M. and Doi, T. (1999) Axially Chiral 1, 7-Naphthyridine-6-Carboxamide Derivatives as Orally Active Tachykinin NK1 Receptor Antagonists: Synthesis, Antagonistic Activity, and Effects on Bladder Functions. Journal of Medicinal Chemistry, 42, 3982-3993. http://dx.doi.org/10.1021/jm990220r

[240]   Frankowski, K.J., Hedrick, M.P., Gosalia, P., Li, K., Shi, S., Whipple, D., Ghosh, P., Prisinzano, T.E., Schoenen, F.J., Su, Y., Vasile, S., Sergienko, E., Gray, W., Hariharan, S., Milan, L., Heynen-Genel, S., Mangravita-Novo, A., Vicchiarelli, M., Smith, L.H., Streicher, J.M., Caron, M.G., Barak, L.S., Bohn, L.M., Chung, T.D.Y. and Aubé, J. (2012) Discovery of Small Molecule Kappa Opioid Receptor Agonist and Antagonist Chemotypes trough a HTS and Hit Refinement Strategy. ACS Chemical Neuroscience, 3, 221-236. http://dx.doi.org/10.1021/cn200128x

[241]   Zheng, M.Q., Nabulsi, N., Kim, S.J., Tomasi, G., Lin, S.F., Mitch, C., Quimby, S., Barth, V., Rash, K., Masters, J., Navarro, A., Seest, E., Morris, E.D. and Carson, R.E. (2013) Synthesis and Evaluation of 11C-LY2795050 as a κ-Opioid Receptor Antagonist Radiotracer for PET Imaging. Journal of Nuclear Medicine, 54, 455-463.

[242]   Urbano, M., Guerrero, M., Rosen, H. and Roberts, E. (2014) Antagonists of the Kappa Opioid Receptor. Bioorganic & Medicinal Chemistry Letters, 24, 2021-2032. http://dx.doi.org/10.1016/j.bmcl.2014.03.040