Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats
2009 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 612, no 1-3, 167-173 p.Article in journal (Refereed) PublishedText
Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 mu g) in a dose-dependent manner with a total blockade at concentraions of 0.4 mu g and 8 mu g for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 mu g). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 mu M)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fast mass in clincal studies.
Place, publisher, year, edition, pages
Elsevier, 2009. Vol. 612, no 1-3, 167-173 p.
Arcuate nucleus, Feeding, Food intake, Growth hormone secretagogue, Hypothalamus, Neuropeptide Y
Social and Clinical Pharmacy Pharmacology and Toxicology
IdentifiersURN: urn:nbn:se:umu:diva-115995DOI: 10.1016/j.ejphar.2009.03.066ISI: 000267150900024PubMedID: 19356720OAI: oai:DiVA.org:umu-115995DiVA: diva2:906842