Involvement of Central Endothelin Receptors in Neonatal Morphine Withdrawal

Abstract

The involvement of central endothelin (ET) receptors in neonatal morphine tolerance has been demonstrated. The present study investigates the role of central ET receptors in morphine withdrawal in neonatal rats. The aim was to determine whether activation of G-proteins coupled to opioid and ET receptors by morphine and various ET receptor modulators is affected during morphine withdrawal in neonatal rats. Pregnant female rats were rendered tolerant to morphine by chronic exposure to morphine pellets during 7 days. On Day 8, pellets were removed and rats were allowed to undergo withdrawal for 24 hrs. Rat pups were delivered by cesarean section. G-protein stimulation induced by morphine; ET-1; the ET_A receptor antagonist, BMS182874; and the ET_B receptor agonist, IRL1620, were determined in the brain of neonatal rats undergoing morphine withdrawal by [³⁵S]GTPγS binding assay. Morphine produced higher (P < 0.05) maximal stimulation of G-protein in the morphine-withdrawal group (83.60%) compared with the placebo group (66.81%). ET-1–induced G-protein stimulation was also altered, and the median effective concentration (EC₅₀) during morphine withdrawal (170.60 nM) was significantly higher than placebo (62.5 nM; P< 0.05). The maximal stimulation induced by the ET_A receptor antagonist, BMS182874, in the morphine-withdrawal group (86.07%; EC₅₀ = 31.25 nM) was significantly higher than in the placebo group (EC₅₀ > 1000 nM). The ET_B agonist, IRL1620, induced G-protein stimulation was similar in placebo (73.43%, EC₅₀ = 13.26 nM) and morphine-withdrawal groups (75.08%, EC₅₀ = 11.70 nM), respectively. To our knowledge, this is the first report indicating involvement of central ET_A receptors in neonatal morphine withdrawal.

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