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Science 3 November 1995:
Vol. 270. no. 5237, pp. 792 - 794
DOI: 10.1126/science.270.5237.792
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Reports

Orphanin FQ: A Neuropeptide That Activates an Opioidlike G Protein-Coupled Receptor

Rainer K. Reinscheid,  Hans-Peter Nothacker,  Anne Bourson,  Ali Ardati,  Robert A. Henningsen,  James R. Bunzow,  David K. Grandy,  Hanno Langen,  Frederick J. Monsma Jr.,  Olivier Civelli (1)

A heptadecapeptide was identified and purified from porcine brain tissue as a ligand for an orphan heterotrimeric GTP- binding protein (G protein)- coupled receptor (LC132) that is similar in sequence to opioid receptors. This peptide, orphanin FQ, has a primary structure reminiscent of that of opioid peptides. Nanomolar concentrations of orphanin FQ inhibited forskolin-stimulated adenylyl cyclase activity in cells transfected with LC132. This inhibitory activity was not affected by the addition of opioid ligands, nor did the peptide activate opioid receptors. Orphanin FQ bound to its receptor in a saturable manner and with high affinity. When injected intracerebroventricularly into mice, orphanin FQ caused a decrease in locomotor activity but did not induce analgesia in the hot-plate test. However, the peptide produced hyperalgesia in the tail-flick assay. Thus, orphanin FQ may act as a transmitter in the brain by modulating nociceptive and locomotor behavior.


R. K. Reinscheid, H.-P. Nothacker, A. Bourson, A. Ardati, R. A. Henningsen, F. J. Monsma Jr., O. Civelli, CNS Research, Pharma Division, Hoffmann-La Roche AG, CH-4002 Basel, Switzerland.
J. R. Bunzow and D. K. Grandy, Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland, OR 97201, USA.
H. Langen, Gene Technologies Research, Pharma Division, Hoffmann-La Roche AG, CH-4002 Basel, Switzerland.
(1) To whom correspondence should be addressed.


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J. Biol. Chem. 277, 31283-31286
   Abstract »    Full Text »    PDF »
Orphanin FQ/Nociceptin-Mediated Desensitization of Opioid Receptor-Like 1 Receptor and {micro} Opioid Receptors Involves Protein Kinase C: A Molecular Mechanism for Heterologous Cross-Talk.
C. D. Mandyam, D. R. Thakker, J. L. Christensen, and K. M. Standifer (2002)
J. Pharmacol. Exp. Ther. 302, 502-509
   Abstract »    Full Text »    PDF »
Morphine-3beta -D-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa.
T. D. Moran and P. A. Smith (2002)
J. Pharmacol. Exp. Ther. 302, 568-576
   Abstract »    Full Text »    PDF »
Characterization of an orphan G protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule.
E. Bender, A. Buist, M. Jurzak, X. Langlois, G. Baggerman, P. Verhasselt, M. Ercken, H.-Q. Guo, C. Wintmolders, I. Van den Wyngaert, et al. (2002)
PNAS 99, 8573-8578
   Abstract »    Full Text »    PDF »
Determinants of Ligand Selectivity at the kappa -Receptor Based on The Structure of the Orphanin FQ Receptor.
C. E. Owens and H. Akil (2002)
J. Pharmacol. Exp. Ther. 300, 992-999
   Abstract »    Full Text »    PDF »
Antioscillatory Effects of Nociceptin/Orphanin FQ in Synaptic Networks of the Rat Thalamus.
S. Meis, T. Munsch, and H.-C. Pape (2002)
J. Neurosci. 22, 718-727
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[Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies.
D. Rizzi, A. Rizzi, R. Bigoni, V. Camarda, G. Marzola, R. Guerrini, C. De Risi, D. Regoli, and G. Calo' (2002)
J. Pharmacol. Exp. Ther. 300, 57-63
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Characterization of Rat Prepro-Orphanin FQ/Nociceptin(154-181): Nociceptive Processing in Supraspinal Sites.
G. C. Rossi, M. Pellegrino, R. Shane, C. A. Abbadie, J. Dustman, C. Jimenez, R. J. Bodnar, G. W. Pasternak, and R. G. Allen (2002)
J. Pharmacol. Exp. Ther. 300, 257-264
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An Opioid System in Connective Tissue: A Study of Achilles Tendon in the Rat.
P. W. Ackermann, M. Spetea, I. Nylander, K. Ploj, M. Ahmed, and A. Kreicbergs (2001)
J. Histochem. Cytochem. 49, 1387-1396
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Pronociceptive Effects of Nociceptin/Orphanin FQ (13-17) at Peripheral and Spinal Level in Mice.
M. Inoue, S. Matsunaga, M. H. Rashid, A. Yoshida, K. Mizuno, T. Sakurada, H. Takeshima, and H. Ueda (2001)
J. Pharmacol. Exp. Ther. 299, 213-219
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Potentiation of Opioid Analgesia in Dopamine2 Receptor Knock-Out Mice: Evidence for a Tonically Active Anti-Opioid System.
M. A. King, S. Bradshaw, A. H. Chang, J. E. Pintar, and G. W. Pasternak (2001)
J. Neurosci. 21, 7788-7792
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Nociceptin inhibits calcium channel currents in a subpopulation of small nociceptive trigeminal ganglion neurons in mouse.
S. L Borgland, M. Connor, and M. J Christie (2001)
J. Physiol. 536, 35-47
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Ovarian Sex Steroid-Dependent Plasticity of Nociceptin/Orphanin FQ and Opioid Modulation of Spinal Dynorphin Release.
D. S. Gupta, A. B. Kelson, W. E. Polgar, L. Toll, M. Szucs, and A. R. Gintzler (2001)
J. Pharmacol. Exp. Ther. 298, 1213-1220
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Nociceptin Reduces Epileptiform Events in CA3 Hippocampus via Presynaptic and Postsynaptic Mechanisms.
M. K. Tallent, S. G. Madamba, and G. R. Siggins (2001)
J. Neurosci. 21, 6940-6948
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The Molecular and Behavioral Pharmacology of the Orphanin FQ/Nociceptin Peptide and Receptor Family.
J. S. Mogil and G. W. Pasternak (2001)
Pharmacol. Rev. 53, 381-415
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Altered Processing of Pro-Orphanin FQ/Nociceptin and Pro-Opiomelanocortin-Derived Peptides in the Brains of Mice Expressing Defective Prohormone Convertase 2.
R. G. Allen, B. Peng, M. J. Pellegrino, E. D. Miller, D. K. Grandy, J. R. Lundblad, C. L. Washburn, and J. E. Pintar (2001)
J. Neurosci. 21, 5864-5870
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Pharmacological Characterization of the Novel Nonpeptide Orphanin FQ/Nociceptin Receptor Agonist Ro 64-6198: Rapid and Reversible Desensitization of the ORL1 Receptor in Vitro and Lack of Tolerance in Vivo.
F. M. Dautzenberg, J. Wichmann, J. Higelin, G. Py-Lang, C. Kratzeisen, P. Malherbe, G. J. Kilpatrick, and F. Jenck (2001)
J. Pharmacol. Exp. Ther. 298, 812-819
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Actions of nociceptin/orphanin FQ and other prepronociceptin products on rat rostral ventromedial medulla neurons in vitro.
C. W Vaughan, M. Connor, E. A Jennings, S. Marinelli, R. G Allen, and M. J Christie (2001)
J. Physiol. 534, 849-859
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Pre- and postsynaptic inhibition by nociceptin in guinea pig small intestinal myenteric plexus in vitro.
S. Liu, H.-Z. Hu, J. Ren, C. Gao, N. Gao, Z. Lin, Y. Xia, and J. D. Wood (2001)
Am J Physiol Gastrointest Liver Physiol 281, G237-G246
   Abstract »    Full Text »    PDF »
Book Review: The Pharmacology of Mu Analgesics: From Patients to Genes.
G. W. Pasternak (2001)
Neuroscientist 7, 220-231
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Control of glutamate and GABA release by nociceptin/orphanin FQ in the rat lateral amygdala.
S. Meis and H.-C. Pape (2001)
J. Physiol. 532, 701-712
   Abstract »    Full Text »    PDF »
Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist.
P. Huang, G. B. Kehner, A. Cowan, and L.-Y. Liu-Chen (2001)
J. Pharmacol. Exp. Ther. 297, 688-695
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Modulation of Synaptic Transmission by Nociceptin/Orphanin FQ and Nocistatin in the Spinal Cord Dorsal Horn of Mutant Mice Lacking the Nociceptin/Orphanin FQ Receptor.
S. Ahmadi, C. Kotalla, H. Gühring, H. Takeshima, A. Pahl, and H. U. Zeilhofer (2001)
Mol. Pharmacol. 59, 612-618
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Effects of orphanin FQ on central dopaminergic neuronal activities and prolactin secretion.
K.-R. Shieh and J.-T. Pan (2001)
Am J Physiol Regulatory Integrative Comp Physiol 280, R705-R712
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Antianalgesic Action of Nociceptin Originating in the Brain Is Mediated by Spinal Prostaglandin E2 in Mice.
J. J. Rady, W. B. Campbell, and J. M. Fujimoto (2001)
J. Pharmacol. Exp. Ther. 296, 7-14
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Tetrapeptide Derivatives of [D-Pen2,D-Pen5]-Enkephalin (DPDPE) Lacking an N-Terminal Tyrosine Residue Are Agonists at the {micro}-Opioid Receptor.
I. J. McFadyen, K. Sobczyk-Kojiro, M. J. Schaefer, J. C. Ho, J. R. Omnaas, H. I. Mosberg, and J. R. Traynor (2000)
J. Pharmacol. Exp. Ther. 295, 960-966
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