Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. (September 2016)

• Record Type: Journal Article
• Authors: Wang, Zi-long; Li, Ning; Wang, Pei; Tang, Hong-hai; Han, Zheng-lan; Song, Jing-jing; Li, Xu-hui; Yu, Hong-ping; Zhang, Ting; Zhang, Run; Xu, Biao; Zhang, Meng-na; Fang, Quan; Wang, Rui
• Is Part Of: Neuropharmacology. Volume 108(2016)
• Page Start: 364
• Page End: 372
• Publication Date: 2016-09
• Subjects: Chimeric peptide -- Endomorphin-2 -- Neuropeptide FF -- Opioid -- Antinociception -- Non-tolerance; ANOVA analysis of variance -- AUC area under the curve -- β-FNA beta-Funaltrexamine -- cAMP cyclic adenosine monophosphate -- CNS central nervous system -- CPA conditioned place aversion -- EN-9 Tyr-Pro-Phe-Phe-Gln-Pro-Gln-Arg-Phe-NH2 -- EM-2 YPFF-NH2 -- EC50 effective concentration 50% of maximum response -- ED50 effective dose 50% of maximum response -- GPCR G-protein-coupled receptor -- IBMX 3-isobutyl-1-methylxanthine -- i.c.v. intracerebroventricularly -- i.v. intravenous -- i.p. intraperitoneal -- %MPE the percent maximum possible effect -- nor-BNI nor-binaltorphimine -- NPFF Phe-Leu-Phe-Glu-Pro-Gln-Arg-Phe-NH2 -- NTI naltrindole -- RF9 1-adamantanecarbonyl-Arg-Phe-NH2 -- s.c. subcutaneous; NPFF (PubChem CID: 123797) -- RF9 (PubChem CID: 53320361) -- endomorphin-2 (PubChem CID: 5311081) -- naloxone (PubChem CID: 5464092) -- beta-Funaltrexamine (PubChem CID: 5311018) -- nor-binaltorphimine (PubChem CID: 5480230) -- naltrindole (PubChem CID: 5497186) -- morphine (PubChem CID: 5288826) -- forskolin (PubChem CID: 47936) -- IBMX (PubChem CID: 3758); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.03.017
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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 κ-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 κ-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 κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects. Highlights: EN-9 is a novel chimeric peptide of Neuropeptide FF and Endomorphin-2. EN-9 is a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. EN-9 significantly produces non-tolerance forming antinociception. EN-9 produces potent antinociception after systemic and peripheral injection. EN-9 produces limited side effects on rewarding and constipation.