N-Methyl-D-aspartate receptor antagonists and the development of tolerance to the discriminative stimulus effects of morphine in rats.
N-Methyl-D-aspartate receptor antagonists and the development of tolerance to the discriminative stimulus effects of morphine in rats.
复制标题
DOI：
--
复制
发表时间：
1999-07
期刊：
影响因子：
--
通讯作者：
A. Bespalov;R. Balster;P. Beardsley
中科院分区：
文献类型：
--
作者：
A. Bespalov;R. Balster;P. Beardsley
一些报告表明，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂防止阿片类药物镇痛耐受的发展。阿片类药物的某些作用，如其辨别性刺激作用，已知对耐受诱导更有抵抗力。在这项研究中，成年雄性Long-Evans大鼠接受训练，以区分3.2 mg/kg皮下注射。使用标准的、两级固定比率10的食物强化方案从水（载体）中获得吗啡。随后，重复吗啡处理（20 mg/kg; 14天b.i.d.）的管理，这诱导耐受性样的剂量效应曲线的吗啡的歧视性刺激和反应率抑制作用。戒断诱导的反应率降低也表明行为依赖。然后用吗啡或其赋形剂与以下竞争性或非竞争性NMDA拮抗剂之一的组合重复处理单独的组：地佐环平（0.1mg/kg i. p.），3-（2-羧基哌嗪-4-基）-1-丙烯基-1-膦酸（D-CPPene; 3和5.6 mg/kg i. p.），依利地尔（17.3mg/kg i. p.），或R（+）-3-氨基-1-羟基-2-吡咯烷酮[（+）-HA-966; 10 mg/kg i. p.]。对吗啡刺激效应的耐受性的形成被eliprodil和高剂量的D-CPPene减弱，但不被地佐环平、低剂量的D-CPPene和R（+）-3-氨基-1-羟基-2-吡咯烷酮减弱。所有拮抗剂阻止耐受吗啡的反应率的影响的诱导。地佐环平和D-CPPene（5.6 mg/kg）似乎也能防止行为依赖的诱导。NMDA拮抗剂可以防止对吗啡的辨别性刺激效应的耐受性，并且可能防止对吗啡的行为依赖效应的耐受性，但是它们对NMDA受体复合物的作用位点赋予了不同的这样做的能力。
Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine's discriminative stimulus and response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R(+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The development of tolerance to morphine's stimulus effects was attenuated by eliprodil and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists prevented the induction of tolerance to morphine's response rate effects. Dizocilpine and D-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so.