Kevin Murphy

Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone

Relaxin-3 is a member of the insulin superfamily. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3. RXFP3 is expressed within the hypothalamic paraventricular nucleus (PVN), an area central to the stress response. The physiological function of relaxin-3 is unknown but previous work suggests a role in appetite control, stimulation of the hypothalamic-pituitary-gonadal axis and stress. Central administration of relaxin-3 induces c-fos expression in the PVN and increases plasma ACTH levels in rats. The aim of this study was to investigate the effect of central administration of human relaxin-3 (H3) on the hypothalamic-pituitary-adrenal (HPA) axis in male rodents in vivo and in vitro. Intracerebroventricular (i.c.v) administration of H3 (5u200anmol) significantly increased plasma corticosterone at 30u200amin following injection compared with vehicle. Intra-PVN administration of H3 (1.8-1620u200apmol) significantly increased plasma ACTH at 1620u200apmol H3 and corticosterone at 180-1620u200apmol H3 at 30u200amin following injection compared with vehicle. The stress hormone prolactin was also significantly raised at 15u200amin post-injection compared with vehicle. Treatment of hypothalamic explants with H3 (10-1000u200anM) stimulated the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), but H3 had no effect on the release of ACTH from in vitro pituitary fragments. These results suggest that relaxin-3 may regulate the HPA axis, via hypothalamic CRH and AVP neurons. Relaxin-3 may act as a central signal linking nutritional status, reproductive function and stress.