Role of endothelin (ET A) receptors in neonatal morphine withdrawal

Abstract

We have previously demonstrated role of central endothelin (ET) receptors in neonatal morphine tolerance. The present study was conducted to investigate involvement of central ET receptors in neonatal rat morphine withdrawal. The aim was to determine activation of G-proteins coupled to opioid and ET receptors by morphine and ET ligands in neonatal rat brains during morphine withdrawal. Pregnant female rats were rendered tolerant to morphine by chronic exposure to morphine pellets over 7 days. Withdrawal was induced on day 8 by removal of pellets. Rat pups were delivered by cesarean section 24 h after pellet removal. G-protein stimulation induced by morphine; ET-1; ET A receptor antagonist, BMS182874; and ET B receptor agonist, IRL1620, was determined in the brain of neonatal rats undergoing morphine withdrawal by [ 35S]GTPγS binding assay. Morphine-induced maximal stimulation of G-protein in morphine withdrawal group (83.60%) was significantly higher compared to placebo control group (66.81%). EC 50 value for ET-1-induced G-protein stimulation during morphine withdrawal (170.60 nM) was higher than control (62.5 nM). BMS182874, did not stimulate GTP binding in control but significantly increased maximal stimulation of G-proteins in morphine withdrawal (86.07%, EC 50 = 31.25 nM). IRL1620-induced stimulation of G-proteins was similar in control and morphine withdrawal. The present findings indicate involvement of central ET A receptors in neonatal morphine withdrawal.