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Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance.
Neuropharmacology. 2016 09; 108:364-72.N

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.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.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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26970017

Citation

Wang, Zi-Long, et al. "Pharmacological Characterization of EN-9, a Novel Chimeric Peptide of Endomorphin-2 and Neuropeptide FF That Produces Potent Antinociceptive Activity and Limited Tolerance." Neuropharmacology, vol. 108, 2016, pp. 364-72.
Wang ZL, Li N, Wang P, et al. Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. Neuropharmacology. 2016;108:364-72.
Wang, Z. L., Li, N., Wang, P., Tang, H. H., Han, Z. L., Song, J. J., Li, X. H., Yu, H. P., Zhang, T., Zhang, R., Xu, B., Zhang, M. N., Fang, Q., & Wang, R. (2016). Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. Neuropharmacology, 108, 364-72. https://doi.org/10.1016/j.neuropharm.2016.03.017
Wang ZL, et al. Pharmacological Characterization of EN-9, a Novel Chimeric Peptide of Endomorphin-2 and Neuropeptide FF That Produces Potent Antinociceptive Activity and Limited Tolerance. Neuropharmacology. 2016;108:364-72. PubMed PMID: 26970017.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. AU - Wang,Zi-Long, AU - Li,Ning, AU - Wang,Pei, AU - Tang,Hong-Hai, AU - Han,Zheng-Lan, AU - Song,Jing-Jing, AU - Li,Xu-Hui, AU - Yu,Hong-Ping, AU - Zhang,Ting, AU - Zhang,Run, AU - Xu,Biao, AU - Zhang,Meng-Na, AU - Fang,Quan, AU - Wang,Rui, Y1 - 2016/03/09/ PY - 2015/11/10/received PY - 2016/03/08/revised PY - 2016/03/08/accepted PY - 2016/3/13/entrez PY - 2016/3/13/pubmed PY - 2017/7/19/medline KW - Antinociception KW - Chimeric peptide KW - Endomorphin-2 KW - IBMX (PubChem CID: 3758) KW - NPFF (PubChem CID: 123797) KW - Neuropeptide FF KW - Non-tolerance KW - Opioid KW - RF9 (PubChem CID: 53320361) KW - beta-Funaltrexamine (PubChem CID: 5311018) KW - endomorphin-2 (PubChem CID: 5311081) KW - forskolin (PubChem CID: 47936) KW - morphine (PubChem CID: 5288826) KW - naloxone (PubChem CID: 5464092) KW - naltrindole (PubChem CID: 5497186) KW - nor-binaltorphimine (PubChem CID: 5480230) SP - 364 EP - 72 JF - Neuropharmacology JO - Neuropharmacology VL - 108 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/26970017/Pharmacological_characterization_of_EN_9_a_novel_chimeric_peptide_of_endomorphin_2_and_neuropeptide_FF_that_produces_potent_antinociceptive_activity_and_limited_tolerance_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(16)30089-2 DB - PRIME DP - Unbound Medicine ER -