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Int. J. Mol. Sci. 2017, 18(8), 1810;

NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents

Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wenhwa 1st Road, Guishan, Taoyuan 333, Taiwan
Department of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan
Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Neuroscience Research Center, Chang Gung Memorial Hospital, No. 5, Fusing St., Guishan, Taoyuan 333, Taiwan
Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
Author to whom correspondence should be addressed.
Received: 9 June 2017 / Revised: 16 August 2017 / Accepted: 18 August 2017 / Published: 21 August 2017
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Neuropeptide FF (NPFF) belongs to the RFamide family and is known as a morphine-modulating peptide. NPFF regulates various hypothalamic functions through two receptors, NPFFR1 and NPFFR2. The hypothalamic-pituitary-adrenal (HPA) axis participates in physiological stress response by increasing circulating glucocorticoid levels and modulating emotional responses. Other RFamide peptides, including neuropeptide AF, neuropeptide SF and RFamide related peptide also target NPFFR1 or NPFFR2, and have been reported to activate the HPA axis and induce anxiety- or depression-like behaviors. However, little is known about the action of NPFF on HPA axis activity and anxiety-like behaviors, and the role of the individual receptors remains unclear. In this study, NPFFR2 agonists were used to examine the role of NPFFR2 in activating the HPA axis in rodents. Administration of NPFFR2 agonists, dNPA (intracerebroventricular, ICV) and AC-263093 (intraperitoneal, IP), time-dependently (in rats) and dose-dependently (in mice) increased serum corticosteroid levels and the effects were counteracted by the NPFF receptor antagonist, RF9 (ICV), as well as corticotropin-releasing factor (CRF) antagonist, α-helical CRF(9-41) (intravenous, IV). Treatment with NPFFR2 agonist (AC-263093, IP) increased c-Fos protein expression in the hypothalamic paraventricular nucleus and induced an anxiogenic effect, which was evaluated in mice using an elevated plus maze. These findings reveal, for the first time, that the direct action of hypothalamic NPFFR2 stimulates the HPA axis and triggers anxiety-like behaviors. View Full-Text
Keywords: neuropeptide FF (NPFF); NPFFR2; HPA axis; anxiety; PVN; CRF neuropeptide FF (NPFF); NPFFR2; HPA axis; anxiety; PVN; CRF

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Lin, Y.-T.; Yu, Y.-L.; Hong, W.-C.; Yeh, T.-S.; Chen, T.-C.; Chen, J.-C. NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents. Int. J. Mol. Sci. 2017, 18, 1810.

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