CAS key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.
CAS key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2023 Dec 20;127:110818. doi: 10.1016/j.pnpbp.2023.110818. Epub 2023 Jun 20.
Although the negative effects coming along with opiate withdrawal are in part modulated by L-type calcium channels (LTCCs), the distinctive physiological properties and functions of LTCCs subtypes suggest differential roles of subtypes during withdrawal. The present study aimed to examine the contributions of LTCC subtypes, Ca1.2 and Ca1.3, within the dorsal hippocampus (DH) in naloxone-precipitated morphine withdrawal using the conditioned place aversion (CPA) paradigm. Firstly, we injected the non-specific LTCCs antagonist verapamil into the DH of morphine-dependent rats before conditioning an environment with naloxone-precipitated withdrawal. Our results showed that verapamil blocked the acquisition of CPA. Then, to explore the molecular mechanisms of LTCCs subtypes during withdrawal, we measured the protein expression of Ca1.2 and Ca1.3 in morphine-dependent rats under different conditions. In morphine-dependent rats, conditioning with withdrawal increased Ca1.2 expression in the membrane, while only acute naloxone injection increased the membrane expression of Ca1.3. To further determine the causal roles of LTCCs subtypes in the withdrawal process, we used Ca1.2 siRNA or Ca1.3 shRNA to knock down the expression of subtypes and detected the effects on CPA and somatic withdrawal signs in morphine-dependent rats. Ca1.2 siRNA, but not Ca1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms. Together, our findings reveal that Ca1.2, but not Ca1.3 plays an important role in mediating morphine withdrawal, suggesting this subtype may serve as a potential therapeutic target for the treatment of negative effects in opiate dependence.
尽管阿片类药物戒断带来的负面影响部分受到 L 型钙通道（LTCCs）的调节，但 LTCCs 亚型的独特生理特性和功能表明，在戒断过程中，亚型可能发挥不同的作用。本研究旨在通过条件性位置厌恶（CPA）范式，在背海马（DH）中检测 LTCC 亚型 Ca1.2 和 Ca1.3 在纳洛酮引发的吗啡戒断中的作用。首先，我们在吗啡依赖大鼠进行条件化环境与纳洛酮引发戒断之前，将非特异性 LTCC 拮抗剂维拉帕米注射到 DH 中。我们的结果表明，维拉帕米阻断了 CPA 的获得。然后，为了探索 LTCC 亚型在戒断过程中的分子机制，我们在不同条件下测量了吗啡依赖大鼠中 Ca1.2 和 Ca1.3 的蛋白表达。在吗啡依赖大鼠中，戒断条件化增加了膜上 Ca1.2 的表达，而只有急性纳洛酮注射增加了膜上 Ca1.3 的表达。为了进一步确定 LTCC 亚型在戒断过程中的因果作用，我们使用 Ca1.2 siRNA 或 Ca1.3 shRNA 敲低亚型的表达，并检测其对吗啡依赖大鼠 CPA 和躯体戒断症状的影响。Ca1.2 siRNA，但不是 Ca1.3 shRNA，抑制了 CPA 的获得并缓解了躯体戒断症状。总之，我们的研究结果表明，Ca1.2 而不是 Ca1.3 对介导吗啡戒断起着重要作用，提示该亚型可能成为治疗阿片类药物依赖负面效应的潜在治疗靶点。
