Abstract
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.
Highlights
The founding member of the RFamide family, FMRF-amide, was originally isolated from the clam, Macrocallista nimbosa, and was reported to be a cardioexcitatory peptide [1]
Both NPFFR1 and NPFFR2 are expressed in various subregions of the hypothalamus, including paraventricular nucleus (PVN), which is upstream of the hypothalamic-pituitary-adrenal (HPA) axis [7,8]
The results suggest that NPFFR2 may inactivate PVN GABA neurons, and as such, it is possible that NPFFR2 evokes hypothalamic corticotropin-releasing factor (CRF) release from parvocellular neurons
Summary
The founding member of the RFamide family, FMRF-amide, was originally isolated from the clam, Macrocallista nimbosa, and was reported to be a cardioexcitatory peptide [1]. NPFF augments GABAergic neurotransmission to magnocellular PVN neurons, inhibiting the downstream release of vasopressin [20] These opposing functions may be attributable to individual receptor activities. Other RF-amide peptides have been reported to regulate the activity of HPA axis and increase the blood corticosteroid (CORT) levels, including NPAF, NPSF, kisspeptin-13 and RFRP-3 [21,22,23,24]. Continuous stimulation of NPFFR2 possibly disrupts the negative feedback pathway of the HPA axis since the expression of hippocampal glucocorticoid receptors was reduced while serum CORT level increased. These mice displayed depressive and anxiety-like behaviors [25]. In an attempt to pinpoint the role of NPFFR2 in HPA axis regulation, NPFFR2 was modulated using pharmacological approaches in rodents, and the effects on HPA axis activity were measured
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