title: The hypothalamic melanocortin system stimulates the hypothalamo-pituitary-adrenal axis in vitro and in vivo in male rats.
abstract: alpha-Melanocyte-stimulating hormone (alpha-MSH) is an agonist, and agouti-related protein (Agrp) an endogenous antagonist at the melanocortin 3 and 4 receptors which are found in the central nervous system (CNS). We have examined the effect of alpha-MSH and Agrp on the hypothalamo-pituitary-adrenal (HPA) axis in vitro and in vivo in male rats. Intraparaventricular nuclear (iPVN) injection of [Nle(4),D-Phe(7)]-alpha-MSH (NDP-MSH) (a long-acting alpha-MSH analogue) increased plasma adrenocorticotropic hormone (ACTH) (10 min post-injection: 25.0 +/- 3.9 vs. saline 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 174.1 +/- 14.2 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05). iPVN injection of Agrp(83-132) increased plasma ACTH (24.2 +/- 4.0 vs. saline 10.1 +/- 1.0 pg/ml, p < 0.01). The combination of NDP-MSH and Agrp(83-132) administered iPVN significantly increased plasma ACTH (10 min post-injection: 21.3 +/- 3.8 vs. 10.9 +/- 2.0, p < 0.05) and plasma corticosterone (10 min post-injection: 169.0 +/- 15.1 vs. saline 124.7 +/- 16.3 ng/ml, p < 0.05), but there was no additive effect. Hypothalamic explants treated with alpha-MSH (100 nM) resulted in a 159 +/- 23% increase in corticotropin-releasing hormone (CRH) release (p < 0.01) and 175 +/- 12% increase in arginine vasopressin (AVP) release (p < 0.001) compared to basal. Agrp(83-132) (100 nM) administered to hypothalamic explants resulted in a 161 +/- 20% increase in CRH (p < 0.01) and 174 +/- 13% increase in AVP release (p < 0.001) compared to basal. Hypothalamic explants treated with the combination of alpha-MSH and Agrp(83-132) (100 nM) resulted in a 179 +/- 31% increase in CRH release (p < 0.01) and 130 +/- 9% increase in AVP release (p < 0.01) compared to basal, but there was no additive effect. This is the first report that both alpha-MSH and Agrp(83-132) stimulate the HPA axis. The combination of alpha-MSH and Agrp(83-132) has no additive effect in vitro and in vivo in male rats. These results suggest that there may be another receptor independent of the known melanocortin receptors at which Agrp is acting.
authors.affiliation: Department of Metabolic Medicine, Imperial College School of Medicine, London, UK.
authors.forename: Waljit S
authors.initials: WS
authors.lastname: Dhillo
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Small
authors.forename: Leighton J
authors.initials: LJ
authors.lastname: Seal
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Stanley
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Murphy
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D054369:Agouti-Related Protein; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004338:Drug Combinations; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007031:Hypothalamus / Q000502:physiology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000502:physiology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D054369:Agouti-Related Protein; D004338:Drug Combinations; D010446:Peptide Fragments; C411703:agouti-related protein-(83-132); D001127:Arginine Vasopressin; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D009074:Melanocyte-Stimulating Hormones; D003346:Corticotropin-Releasing Hormone