Studies on the mechanism of morphine tolerance

吗啡耐受机制的研究

• 批准号: 02670896
• 负责人: MATSUMOTO Ken
• 金额: $ 1.34万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02670896/
• 关键词: Morphine; Calcium Channel; Potassium Channel; GTP-binding Protein; モルヒネの作用機序; カルシウム拮抗剤; 培養神経芽細胞腫細胞; Morphine; Calcium channel; GTP γS; tolerance; hippocampus

In the present study, we examined the mechanism of the action of morphine and morphine tolerance focusing on calcium dynamics. In rat hippocampal electrophysiological study, morphine enhanced the field potentials evoked in CA1 pyramidal cells. GTPgammaS, the analogue of GTP which activates GTP-binding proteins, inhibited the effect of morphine dose-dependently. It was also observed that morphine converted the aff inity of ^3H-nitrendipine binding to calcium channels to a low affinity state in rat hippocampal membrane fractions. On the other hand, the binding of ^3H-nitrendipine to the cortical membrane fractions in rodents were enhanced about 30% following chronic treatment of morphine without the alteration of affinity. Intracerebroventricular treatment of pertussis toxin, in which inactivates GTP-binding proteins, showed the similar results to morphine tolerance. These results suggested that the enhancement of calcium influx which caused by the inactivation of GTP-binding proteins had the important role of the morphine tolerance.In 1991, we examined the effects of morphine on the intracellular concentration of calcium ([Ca^<2+>]i) in Fura-2 loaded human neuroblastoma cell SH-SY5Y. It was observed that 10^<-6> - 10^<-4>M morphine inhibited dose-dependently the carbachol-induced increment of [Ca^<2+>]i. Nifedipine, a calcium channel blocker, also inhibited this increment of [Ca^<2+>]i. Furthermore, nifedipine showed the same effect to KCL-induced increase of [Ca^<2+>]i whereas morphine had no effect. These results showed that morphine inhibits calcium influx through K-channels in this neuroblastoma cell. In conclusion, (1)morphine decreased the affinity of calcium channels through K-channels therby inhibits calcium influx intonerve terminals. (2)Following chronic treatment of morphine, the regulation of calcium dynamics probably altered by inactivation of pertussis toxin-sensitive GTP-binding proteins.

在本研究中，我们研究了吗啡和吗啡耐受的作用机制，重点是钙动力学。在大鼠海马电生理研究中，吗啡可增强海马CA 1区锥体细胞诱发的场电位。激活GTP结合蛋白的GTP类似物GTP γ S剂量依赖性地抑制吗啡的作用。我们还观察到，在大鼠海马膜组分中，吗啡将^3H-尼群地平与钙通道结合的亲和力转变为低亲和力状态。另一方面，在啮齿类动物中，长期给予吗啡后，^3H-尼群地平与皮质膜组分的结合增强了约30%，而亲和力没有改变。脑室内注射百日咳毒素可使GTP结合蛋白失活，其结果与吗啡耐受相似。1991年，我们观察了吗啡对Fura-2负载的人神经母细胞瘤细胞SH-SY 5 Y胞内钙离子浓度（[Ca^（2+）]i）的影响。10^<-6>- 10^<-4>M吗啡剂量依赖性地抑制卡巴胆碱引起的[Ca^&lt;2+&gt;]i增加。钙通道阻滞剂硝苯地平也能抑制[Ca^&lt;2+&gt;]i的增加。硝苯地平对KCl引起的[Ca^2+]i升高也有同样的作用，而吗啡则无此作用。这些结果表明，吗啡抑制钙内流通过K-通道在这个神经母细胞瘤细胞。结论：（1）吗啡通过K通道降低钙通道亲和力，从而抑制神经末梢钙内流。（2）吗啡慢性作用后，百日咳毒素敏感性GTP结合蛋白失活，改变了钙动力学的调节。

项目成果

T.Ohnishi et al.: "Intracerebroventricular treatment of mice with pertussis toxin induces hyperalgesia and enhances ^3H-nitrendipine binding to synaptic membranes" Naunyn-Schmied.Arch.Pharmacol.341. 123-127 (1990)

T.Ohnishi 等人：“用百日咳毒素对小鼠进行侧脑室治疗可诱导痛觉过敏并增强 3H-尼群地平与突触膜的结合”Naunyn-Schmied.Arch.Pharmacol.341。

K. Saito: "Effect of GTPgammaS on the action of morphine in hippocampal slices" Eur. J. Pharmacol.183(6). 2313-2314 (1990)

K. Saito：“GTPgammaS 对海马切片中吗啡作用的影响”Eur。

T.Ohnishi et al.: "The effect of GTP rS on the action of morphine in rat hippocampus" pharmacol.Comm.(1992)

T.Ohnishi 等人：“GTP rS 对大鼠海马吗啡作用的影响”pharmacol.Comm.(1992)

K.Saito et al.: "Effect of GTP rS on the action of morphine in hippocampal slices" Eur.J.Pharmacol.183(6). 2313-2314 (1990)

K.Saito 等人：“GTP rS 对海马切片中吗啡作用的影响”Eur.J.Pharmacol.183(6)。

K. Saito: "The mechanism of morphine analgesia" Processing and Inhibition of Nociceptive Information. Excerpta Medica Processing and Inhibition of Nociceptive Information. 83-87 (1992)

K. Saito：“吗啡镇痛机制”伤害感受信息的处理和抑制。