NPFFR2 Activates the HPA Axis and Induces Anxiogenic Effects in Rodents

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.

Ablation of NPFFR2 in Mice Reduces Response to Single Prolonged Stress Model

“…The unique phenotype related to the HPA axis in PTSD patients has been difficult for researchers to recapitulate in PTSD animal models [ 24 ]. Nevertheless, our findings are supported by previous reports that NPFFR2 signals are important to stress-induced HPA axis hyperactivity and emotional responses [ 14 , 15 ].…”

“…However, the impact of NPFF has only begun to be explored in recent years. NPFFR2 has been demonstrated to directly activate the HPA axis through the hypothalamic PVN, triggering anxiety-like behaviors [ 12 , 14 ]. In the current study, we verified the impact of NPFFR2 knockdown on stress-related disorders.…”

“…One of its major receptors, NPFF receptor 2 (NPFFR2), is expressed in various sub-regions of the hypothalamus, including the PVN [ 13 ]. Correspondingly, pharmacological activation of NPFFR2 directly stimulates the HPA axis through the PVN, which increases c-Fos protein expression in the PVN, causing downstream CORT secretion and anxiety-like behaviors [ 14 ]. Both NPFFR2-overexpressing mice and mice chronically administered with NPFFR2 agonist exhibit depressive-like behaviors and biochemical changes that are similar to mice exposed to chronic stress [ 15 ].…”

Role of the Hypothalamic–Pituitary–Adrenal Axis in Health and Disease

“…Next, in a research article by Lin et al [ 6 ], the effects of Neuropeptide FF (NPFF) on the HPA axis and subsequent development of anxiety-like behaviors in rodents were assessed. Central NPFF, via activation of the NPFF receptor 2, increases HPA axis activity as assessed by serum corticosteroid levels.…”

Identification of a 3‑mRNA signature as a novel potential prognostic biomarker in patients with ovarian serous cystadenocarcinoma in G2 and G3

“…A similar pattern is observed in the pathological grading and staging of head and neck squamous cell carcinoma; the degree of malignancy was directly proportional to that of NPFFR2 methylation (29). NPFFR2 is also associated with the activity of hypothalamic-pituitary-adrenal axis (30). In terms of stress-associated hormones and released neurotransmitters, quality has an adverse effect on stress-induced tumor progression and cancer treatment (31), which indirectly indicate that the progression of cancer (increased histological grade, etc.)…”