Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
Addict Biol. 2011 Oct;16(4):551-64. doi: 10.1111/j.1369-1600.2010.00269.x. Epub 2010 Dec 23.
We investigated possible alterations of pharmacologically-isolated, evoked GABA(A) inhibitory postsynaptic potentials (eIPSPs) and miniature GABA(A) inhibitory postsynaptic currents (mIPSCs) in the rat central amygdala (CeA) elicited by acute application of µ-opioid receptor (MOR) agonists (DAMGO and morphine; 1 µM) and by chronic morphine treatment with morphine pellets. The acute activation of MORs decreased the amplitudes of eIPSPs, increased paired-pulse facilitation (PPF) of eIPSPs and decreased the frequency (but not the amplitude) of mIPSCs in a majority of CeA neurons, suggesting that acute MOR-dependent modulation of this GABAergic transmission is mediated predominantly via presynaptic inhibition of GABA release. We observed no significant changes in the membrane properties, eIPSPs, PPF or mIPSCs of CeA neurons during chronic morphine treatment compared to CeA of naïve or sham rats. Superfusion of the MOR antagonist CTOP (1 µM) increased the mean amplitude of eIPSPs in a majority of CeA neurons to the same degree in both naïve/sham and morphine-treated rats, suggesting a tonic activation of MORs in both conditions. Superfusion of DAMGO decreased eIPSP amplitudes and the frequency of mIPSCs equally in both naïve/sham and morphine-treated rats but decreased the amplitude of mIPSCs only in morphine treated rats, an apparent postsynaptic action. Our combined findings suggest the development of tolerance of the CeA GABAergic system to inhibitory effects of acute activation of MORs on presynaptic GABA release and possible alteration of MOR-dependent postsynaptic mechanisms that may represent important neuroadaptations of the GABAergic and MOR systems during chronic morphine treatment.
我们研究了在大鼠杏仁中央核（CeA）中，急性应用μ-阿片受体（MOR）激动剂（DAMGO 和吗啡；1 μM）和慢性吗啡贴片处理对药理学分离的、诱发的 GABA(A) 抑制性突触后电位（eIPSP）和微小 GABA(A) 抑制性突触后电流（mIPSCs）可能产生的改变。MOR 的急性激活降低了 eIPSP 的幅度，增加了 eIPSP 的成对脉冲易化（PPF），并降低了 mIPSCs 的频率（但不影响幅度），这表明急性 MOR 依赖性对这种 GABA 能传递的调制主要通过 GABA 释放的突触前抑制来介导。与未处理或假处理的大鼠的 CeA 相比，在慢性吗啡处理期间，我们没有观察到 CeA 神经元的膜特性、eIPSP、PPF 或 mIPSCs 发生显著变化。MOR 拮抗剂 CTOP（1 μM）的灌流使大多数 CeA 神经元的 eIPSP 平均幅度在未处理/假处理和吗啡处理的大鼠中增加到相同程度，这表明在两种情况下 MOR 都处于紧张激活状态。DAMGO 的灌流以相同的程度降低了未处理/假处理和吗啡处理的大鼠中 eIPSP 的幅度和 mIPSCs 的频率，但仅降低了吗啡处理的大鼠中 mIPSCs 的幅度，这是一种明显的突触后作用。我们的综合发现表明，CeA GABA 能系统对 MOR 急性激活对突触前 GABA 释放的抑制作用产生了耐受性，并且可能改变了 MOR 依赖性的突触后机制，这可能代表了慢性吗啡处理期间 GABA 能和 MOR 系统的重要神经适应。
