Leck K J, Bartlett S E, Smith M T, Megirian D, Holgate J, Powell K L, Matthaei K I, Hendry I A
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
Neuropharmacology. 2004 May;46(6):836-46. doi: 10.1016/j.neuropharm.2003.11.024.
The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse develops significantly increased tolerance to morphine, which depends on Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.
对吗啡产生耐受性的潜在机制仍未完全清楚。吗啡与阿片受体结合，进而通过异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）激活下游第二信使级联反应。在本文中，我们表明G(z)（抑制性G蛋白家族的一员）在耐受性形成后介导吗啡的镇痛和致死作用中发挥重要作用。我们通过基因敲除小鼠G蛋白α亚基来阻断通过G(z)第二信使级联反应的信号传导。Gα(z)基因敲除小鼠对吗啡的耐受性显著增加，这取决于Gα(z)基因剂量。进一步实验表明，增强的吗啡耐受性并非由药代动力学和行为学习机制引起。结果提示，G(z)信号通路参与慢性吗啡治疗后吗啡镇痛和致死作用的转导。
