Brain Melanocortin Receptors are Involved In CRH-Mediated HPA Axis Activity And Thermogenesis

Abstract

Recent studies indicate that corticotropin-releasing hormone (CRH) acts down-stream from brain melanocortin receptors (MC-Rs), however, much older evidence actually suggested the opposite. To reconcile this, rats were chroni- cally infused centrally with the MC-R antagonist SHU9119 (0.5 nmol/day) over 14 days. Acute central CRH administra- tion (0.5 μg) caused temporal anorexia, which was not impaired by SHU9119 treatment relative to controls. SHU9119 treatment, however, did attenuate CRH-induced plasma ACTH and thermogenic responses. Since SHU9119 pair-fed rats showed generally similar effects as SHU9119-treated ad libitum feeding rats, the modulation of ACTH and thermogenic responses are not secondary to increased body weight by SHU9119 treatment. Central pre-treatment with the glucocorti- coid receptor agonist dexamethasone (10 μg) before CRH demonstrated that the inhibitory effect of SHU9119 treatment on the CRH-induced ACTH response was not attributed to increased glucocorticoid feedback. Peripheral dexamethasone pre-treatment (25 μg/kg rat), on the other hand, more potently suppressed CRH-induced corticosterone responses in SHU9119-treated rats. This effect is explained by sensitization of the adrenal cortex to glucocorticoid feedback as a result of SHU9119 treatment. We conclude that MC-Rs act down-stream from CRH to facilitate CRH-induced HPA axis activa- tion and thermogenesis, but not down-stream from CRH to facilitate anorexia.