長期給予母鼠嗎啡對其所生幼鼠腦中NMDA受體表現和腦部興奮性的影響以及Dextromethorphan對幼鼠由naloxone誘導嗎啡脫癮症狀的影響

he effect of chronic treatment of morphine on the expression of the NMDA receptor and excitability in the developmental rat brain. The effect of dextromethorphan on morphine withdrawal syndrome.

徐高利(Sheu Gau-Lih)

指導教授 ： 葉健全

臺北醫學大學/醫學院/醫學科學研究所/碩士(1998年)

摘要

懷孕婦女對嗎啡的濫用會造成其新生兒呈現脫癮症狀如發抖或易怒不安(irritable)，且 他們於學齡兒童時期的環境適應及情緒控制能力較差。然而，其病理機制仍舊不清楚。在 動物的實驗中，大白鼠於胚胎期或其母親懷孕期暴露於嗎啡也會產生一些不良影響如腦神 經發育遲緩及腦中生化物質、神經傳導物質或接受器的改變等。過去，我們給予母鼠嗎啡 ，然後檢驗其幼鼠全腦N-Methyl D-Aspartate (NMDA) recep6-揶K度變化情形。結果嗎啡 組在第14天時的NMDA receptor密度比對照組低29%，但在第0、5、30天時兩組間並無統計 上的差異。為更進一步瞭解此密度的改變是發生在腦部那一區域，我們使用3H-{N-[1(2-t hienyl)-cyclohexyl]3,4-piperidine ([3H]-TCP)與幼鼠大腦皮質、海馬回及紋狀體的神 經細胞膜作結合。對照組幼鼠大腦皮質及海馬回的NMDA receptor密度在第14天時達到最 高，而第7、30和60天時之密度並沒有統計上的差異。而最大的不同點為嗎啡組並無此高 峰性的密度變化，嗎啡組在第14天時大腦皮質及海馬回NMDA receptor密度分別比對照組 低23.7%及26.8%，但在第7、30及60天時兩組間並無明顯差異。我們想進一步瞭解長期曝 露於嗎啡下之幼鼠其興奮性是否改變，而使用kainic acid (KA)誘導幼鼠產生抽筋。結果 發現嗎啡組幼鼠在第14天時，達到全身抽筋症狀的隻數比例比對照組高45.5%，而在第7天 、第30天及第60天時，兩組間的比例則沒有統計上的差異。而且在症狀出現的潛伏期及次 數方面，兩組間也沒有統計上的差異。另外，最近學者研究顯示止咳藥之一的dextrometh orphan可以抑制大白鼠長期接受嗎啡後由naloxone誘導的脫癮症狀。我們想暸解dextrome thorphan在幼鼠身上是否有相同的效果。我們長期給予母鼠嗎啡，然後，給予其出生後第 7天幼鼠dextromethorphan，再以naloxone來誘導脫癮症狀產生。結果發現dextromethorp han對長期給予母鼠嗎啡所生之幼鼠由naloxone誘導之脫癮症狀有顯著的抑制效果。

關鍵字

NMDA ； 嗎啡 ； 幼鼠 ； dextromethorphan ； 脫癮

並列摘要

Children born to morphine or heroin addicted mothers have been shown to suffer acute withdrawal syndrome after birth and develop a long-term neuropsychologi cal sequels. Considerable evidences have confirmed that prenatal exposure to m orphine also produce significant alteration in developing brain including reta rdation in neurite growth, change in neurotransm?揶r release and the expressi on of receptors. Our previous study has shown that combined prenatal- and post -natal exposure to morphine induced an age-dependent decrease in the density o f the N-methyl-D-aspartate (NMDA) receptor in the developing rat brain. To fur ther explore the region-specificity of this alteration in the ontogeny of the NMDA receptor I used [3H] [1(2-thienyl)-cyclohexyl]3,4-piperidine ([3H]-TCP) , a ligand that bound to NMDA receptor-coupled ion channel, to quantify the den sities of NMDA receptor on the crude membrane prepared from cortex, hippocamp us and striatum of rats born to dams rats received chronic treatment of morphi ne. I found that morphine group rats have a density of the NMDA receptor in co rtex and hippocampus 23.7% and 26.8% lower than that of control groups on post natal day (PND) 14 only but not on other examined PND. However, no significant difference between these two group of rats in striatum was found. I further d etermined whether alteration in the ontogeny of the NMDA receptor will alter t he excitability of brain, I used kainic acid (KA) to induce seizure behavior i n both control and morphine group rats as a parameter in reflecting the excita bility in these brains. The result showed that morphine rats presented an incr eased sensitivity to KA on PND 14 but on other examined PND. I further determi ned the effect of dextromethorphan (DM), an NMDA receptor channel blocker, in attenuating naloxone-precipitated withdrawal syndrome, manifested as abdominal stretching, in morphine group rats. The result showed that DM with dose of 20 or 30 mg/kg subcutaneous injection decreased the frequency and latency of nal oxone-induced abdominal stretching of morphine group rats on PND 7. These resu lts suggested that prenatal and post-natal morphine exposure will induce alter ation in a age-dependent and region-dependent alteration in the ontogeny of th e NMDA receptor and brain excitability. Whether this alteration will bring imp act on the development of normal brain functions required further investigatio n.

並列關鍵字

NMDA ； morphine ； neonatal rat ； dextromethorphan ； withdrawal