Zhang Die, Zhang Hai, Jin Guo-Zhang, Zhang Kehong, Zhen Xuechu
State Key Laboratory of Drug Research, Department of Neuropharmacology, Shanghai Institute of Material Medica, Chinese Academy of Sciences, Shanghai, PR China.
Mol Pain. 2008 Nov 17;4:57. doi: 10.1186/1744-8069-4-57.
Clinical observation and experimental studies have indicated that a single exposure to morphine could induce tolerance and dependence. It has become a concern in clinical antinociceptive practice. However, the underling mechanism remains unknown. This study was designed to explore the changes of dopamine (DA) neuron activities in the ventral tegmental area (VTA) by employing a spectral analysis followed single morphine treatment.
Acute morphine treatment significantly increased not only the firing rate and firing population but also the power of slow oscillation of DA neurons in naïve rats. These changes lasted at least for 3 days following the morphine treatment. During this period of time, responses of the DA neurons to subsequent morphine challenge were diminished. We further demonstrated a transient desensitization of opiate receptors as monitored by GTPgammaS binding to G-proteins. The present study provided first direct evidence for the temporal changes in the VTA DA neuron activities and opiate receptors desensitization.
Prolonged VTA DA neuron activation and opiate receptors desensitization followed single morphine exposure may underlie the development of dependence and tolerance that may associate with the acute analgesic tolerance and acute addiction of morphine.
临床观察和实验研究表明,单次接触吗啡可诱导耐受性和依赖性。这已成为临床抗伤害感受实践中的一个关注点。然而,其潜在机制仍不清楚。本研究旨在通过采用频谱分析方法,在单次给予吗啡治疗后,探索腹侧被盖区(VTA)多巴胺(DA)神经元活动的变化。
急性吗啡治疗不仅显著增加了未用药大鼠中DA神经元的放电频率和放电群体,还增加了其慢振荡的功率。这些变化在吗啡治疗后至少持续3天。在此期间,DA神经元对随后吗啡激发的反应减弱。我们进一步证明了通过GTPγS与G蛋白结合监测到的阿片受体的短暂脱敏。本研究首次为VTA DA神经元活动的时间变化和阿片受体脱敏提供了直接证据。
单次吗啡暴露后VTA DA神经元的长期激活和阿片受体脱敏可能是依赖性和耐受性发展的基础,这可能与吗啡的急性镇痛耐受性和急性成瘾有关。