Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin-2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance.
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
[Article]
Neuropharmacology.
108:364-372, September 2016.
(Format: HTML, PDF)
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.
Highlights:
* EN-9 is a novel chimeric peptide of Neuropeptide FF and Endomorphin-2.
* EN-9 is a multifunctional agonist of [kappa]-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.
(C) 2016Elsevier, Inc.