Gonadotropin‐Inhibitory Hormone (GnIH) and Its Receptor GPR147 Mediates Acute Stress‐Induced Activation of the Locus Coeruleus‐SAM Axis

ABSTRACT Gonadotropin‐inhibitory hormone (GnIH, also known as RFamide‐related peptide‐3, RFRP‐3) is a hypothalamic neuropeptide that regulates vertebrate reproduction via its receptor GPR147. Although GnIH is known to mediate stress‐induced reproductive suppression, its role in broader stress responses remains unclear. This study investigated the fuction of GnIH in acute stress and evaluated the mechanisms by which GnIH regulates norepinephrine (NE) release and activates the locus coeruleus‐sympathetic‐adrenal medulla (LC‐SAM) axis in mice. The results show that GnIH is co‐localized and co‐stored with NE in sympathetic nerve terminals and that it is associated with heightened LC‐SAM axis activity induced by acute stressors. Central or peripheral administration of GnIH potentiated acute stress responses and activated the LC‐SAM axis, accompanied by increased anxiety‐like behaviors. Conversely, genetic ablation of GnIH or GPR147 attenuated acute stress‐induced anxiety‐like behaviors and LC‐SAM axis activation. Mechanistically, both central and peripheral GnIH enhanced NE synthesis, transport and release. These findings indicate that GnIH mimics or augments endogenous NE signaling to activated the LC‐SAM axis during acute stress. Pharmacological modulation of the GnIH/GPR147 system may represent a therapeutic approach for the inhibiting maladaptive stress responses and stress‐related pathologies and infertility.