Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain.
Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain.
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噻奈普汀在神经性疼痛小鼠模型中促进持久的抗异常疼痛作用。
DOI：
10.1038/s41386-023-01645-w
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Zachariou,Venetia
中科院分区：
文献类型：
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作者：
Serafini,RandalA;Estill,Molly;Pekarskaya,ElizabethA;Sakloth,Farhana;Shen,Li;Javitch,JonathanA;Zachariou,Venetia
三环类抗抑郁药 (TCA)，例如地昔帕明 (DMI)，可有效控制神经性疼痛症状，但通常需要数周时间才能发挥作用，并且还会导致相当大的副作用。噻奈普汀 (TIAN) 是一种非典型抗抑郁药，可激活 mu-阿片受体，但在临床相关剂量下不会在小鼠中产生镇痛耐受或戒断，也不会在人类中产生欣快感。在这里，我们评估了 TIAN 在神经性疼痛的幸存神经损伤 (SNI) 模型中持续缓解机械异常性疼痛的功效，甚至在药物清除后也是如此。在发现与 DMI 相比抗异常疼痛作用起效更快后，我们使用转基因小鼠来深入了解 RGS 蛋白相关通路，这些通路调节 TIAN 相对于 DMI 在神经性疼痛模型中的功效。由于我们在 RGS4、RGSz1 和 RGS9 敲除小鼠中观察到对 TIAN 和 DMI 治疗的相似行为反应，因此我们在延长 SNI 后对 TIAN 和 DMI 治疗的小鼠的 NAc 进行了 RNA 测序，以进一步阐明 TIAN 更快治疗作用的潜在机制。我们的生物信息分析揭示了两种药物之间不同的转录组特征，其中 TIAN 更直接地逆转 SNI 诱导的差异表达基因，并进一步预测了可能与起效有关的几个上游调节因子。对 TIAN 作用分子途径的新认识可能有助于开发新的、更有效的药理学方法来治疗神经性疼痛。
Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain.