PMID- 26970017 OWN - NLM STAT- MEDLINE DCOM- 20170718 LR - 20180207 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 108 DP - 2016 Sep TI - Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. PG - 364-72 LID - S0028-3908(16)30089-2 [pii] LID - 10.1016/j.neuropharm.2016.03.017 [doi] AB - Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of kappa-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by kappa-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of kappa-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects. CI - Copyright (c) 2016. Published by Elsevier Ltd. FAU - Wang, Zi-Long AU - Wang ZL AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Li, Ning AU - Li N AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Wang, Pei AU - Wang P AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Tang, Hong-Hai AU - Tang HH AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Han, Zheng-Lan AU - Han ZL AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Song, Jing-Jing AU - Song JJ AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Li, Xu-Hui AU - Li XH AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Yu, Hong-Ping AU - Yu HP AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Ting AU - Zhang T AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Run AU - Zhang R AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Xu, Biao AU - Xu B AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Zhang, Meng-Na AU - Zhang MN AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. FAU - Fang, Quan AU - Fang Q AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. Electronic address: fangq@lzu.edu.cn. FAU - Wang, Rui AU - Wang R AD - Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. Electronic address: wangrui@lzu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160309 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Analgesics) RN - 0 (Analgesics, Opioid) RN - 0 (EN-9 chimeric peptide) RN - 0 (Oligopeptides) RN - 0 (Peptide Fragments) RN - 0 (Peptides) RN - 0 (Receptors, Neuropeptide) RN - 0 (Receptors, Opioid, kappa) RN - 0 (neuropeptide FF receptor) RN - 3PH5M0466G (endomorphin 2) RN - 99566-27-5 (phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide) SB - IM MH - Analgesics/administration & dosage/chemistry MH - Analgesics, Opioid/*administration & dosage/chemistry MH - Animals MH - Dose-Response Relationship, Drug MH - Drug Tolerance/physiology MH - HEK293 Cells MH - Humans MH - Injections, Intraventricular MH - Male MH - Mice MH - Oligopeptides/*administration & dosage/chemistry MH - Pain Measurement/*drug effects/methods MH - Peptide Fragments/*administration & dosage/chemistry MH - Peptides/*administration & dosage/chemistry MH - Receptors, Neuropeptide/agonists/physiology MH - Receptors, Opioid, kappa/agonists/physiology OTO - NOTNLM OT - Antinociception OT - Chimeric peptide OT - Endomorphin-2 OT - IBMX (PubChem CID: 3758) OT - NPFF (PubChem CID: 123797) OT - Neuropeptide FF OT - Non-tolerance OT - Opioid OT - RF9 (PubChem CID: 53320361) OT - beta-Funaltrexamine (PubChem CID: 5311018) OT - endomorphin-2 (PubChem CID: 5311081) OT - forskolin (PubChem CID: 47936) OT - morphine (PubChem CID: 5288826) OT - naloxone (PubChem CID: 5464092) OT - naltrindole (PubChem CID: 5497186) OT - nor-binaltorphimine (PubChem CID: 5480230) EDAT- 2016/03/13 06:00 MHDA- 2017/07/19 06:00 CRDT- 2016/03/13 06:00 PHST- 2015/11/10 00:00 [received] PHST- 2016/03/08 00:00 [revised] PHST- 2016/03/08 00:00 [accepted] PHST- 2016/03/13 06:00 [entrez] PHST- 2016/03/13 06:00 [pubmed] PHST- 2017/07/19 06:00 [medline] AID - S0028-3908(16)30089-2 [pii] AID - 10.1016/j.neuropharm.2016.03.017 [doi] PST - ppublish SO - Neuropharmacology. 2016 Sep;108:364-72. doi: 10.1016/j.neuropharm.2016.03.017. Epub 2016 Mar 9.