Puppala Bhagya L, Bhalla Shaifali, Matwyshyn George, Gulati Anil
Department of Pediatrics and Neonatology, Advocate Lutheran General Children's Hospital, Park Ridge, Illinois 60068, USA.
Exp Biol Med (Maywood). 2006 Jun;231(6):1157-60.
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]GTPgammaS 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%, EC(50) = 11.70 nM), respectively. To our knowledge, this is the first report indicating involvement of central ET(A) receptors in neonatal morphine withdrawal.
中枢内皮素（ET）受体参与新生大鼠吗啡耐受性已得到证实。本研究探讨中枢ET受体在新生大鼠吗啡戒断中的作用。目的是确定在新生大鼠吗啡戒断期间，吗啡及各种ET受体调节剂对与阿片受体和ET受体偶联的G蛋白的激活是否受到影响。怀孕的雌性大鼠通过在7天内慢性暴露于吗啡丸剂而产生吗啡耐受性。在第8天，取出丸剂，让大鼠进行24小时的戒断。通过剖宫产分娩大鼠幼崽。通过[35S]GTPγS结合试验测定在经历吗啡戒断的新生大鼠脑中，吗啡、ET-1、ET(A)受体拮抗剂BMS182874和ET(B)受体激动剂IRL1620诱导的G蛋白刺激。与安慰剂组（66.81%）相比，吗啡戒断组中吗啡对G蛋白的最大刺激更高（P < 0.05）（83.60%）。ET-1诱导的G蛋白刺激也发生了改变，吗啡戒断期间的半数有效浓度（EC50）（170.60 nM）显著高于安慰剂组（62.5 nM；P < 0.05）。ET(A)受体拮抗剂BMS182874在吗啡戒断组中诱导的最大刺激（86.07%；EC50 = 31.25 nM）显著高于安慰剂组（EC50 > 1000 nM）。ET(B)激动剂IRL1620诱导的G蛋白刺激在安慰剂组（73.43%，EC50 = 13.26 nM）和吗啡戒断组（75.08%，EC50 = 11.70 nM）中分别相似。据我们所知，这是第一份表明中枢ET(A)受体参与新生大鼠吗啡戒断的报告。
