HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling.
HDAC6 Inhibition Reverses Cisplatin-Induced Mechanical Hypersensitivity via Tonic Delta Opioid Receptor Signaling.
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DOI：
10.1523/jneurosci.1182-22.2022
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发表时间：
2022-10-19
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化疗药物顺铂诱导的外周神经性疼痛在治疗后可能持续数月至数年。组蛋白去乙酰化酶6（HDAC6）抑制剂对顺铂诱导的神经性疼痛具有治疗潜力，因为它们在啮齿动物模型中能持续逆转机械性痛觉过敏和自发性疼痛。在此，我们研究了在顺铂最后一次给药3天后给予HDAC6抑制剂治疗2周，雄性和雌性小鼠机械性痛觉过敏逆转的潜在机制。单次注射中性阿片受体拮抗剂6β - 纳曲醇或外周限制性阿片受体拮抗剂甲基纳曲酮可使接受HDAC6抑制剂治疗的两性动物的机械性痛觉过敏暂时恢复。这些结果表明，外周阿片配体 - 受体的强直性信号传导介导了HDAC6抑制剂治疗后顺铂诱导的机械性痛觉过敏的逆转。δ阿片受体（DORs）具有特定作用，顺铂给药后，背根神经节（DRG）神经元中Oprd1表达降低，但经HDAC6抑制剂治疗后恢复正常。单次注射DOR拮抗剂纳曲吲哚可使两性动物的机械性痛觉过敏暂时恢复。同样，当从阿德维林阳性神经元中基因敲除DORs时，HDAC6抑制不能逆转顺铂诱导的痛觉过敏。单次注射针对DOR配体甲硫氨酸 - 脑啡肽的中和抗体也可使两性动物的机械性痛觉过敏暂时恢复。总之，我们揭示了HDAC6抑制剂治疗可诱导外周感觉神经元中的强直性脑啡肽 - DOR信号传导，从而抑制机械性痛觉过敏。
重要声明
超过四分之一的癌症幸存者患有难治性的化疗诱导的外周神经病理性疼痛（CIPN），这种疼痛在治疗结束后可能持续数月至数年。HDAC6抑制是一种逆转CIPN且不会对肿瘤生长产生负面影响的新策略，但对其持续逆转的机制尚不清楚。我们基于内源性阿片系统有助于神经损伤或炎症引起的疼痛的自发性、明显缓解（称为潜在致敏）这一证据进行研究。我们发现，在接受HDAC6抑制剂治疗的小鼠中，阻断δ阿片受体或其配体脑啡肽可揭示CIPN（潜在致敏）。我们的工作为HDAC6抑制剂治疗明显逆转CIPN的机制提供了见解。
Peripheral neuropathic pain induced by the chemotherapeutic cisplatin can persist for months to years after treatment. Histone deacetylase 6 (HDAC6) inhibitors have therapeutic potential for cisplatin-induced neuropathic pain since they persistently reverse mechanical hypersensitivity and spontaneous pain in rodent models. Here, we investigated the mechanisms underlying reversal of mechanical hypersensitivity in male and female mice by a 2 week treatment with an HDAC6 inhibitor, administered 3 d after the last dose of cisplatin. Mechanical hypersensitivity in animals of both sexes treated with the HDAC6 inhibitor was temporarily reinstated by a single injection of the neutral opioid receptor antagonist 6β-naltrexol or the peripherally restricted opioid receptor antagonist naloxone methiodide. These results suggest that tonic peripheral opioid ligand-receptor signaling mediates reversal of cisplatin-induced mechanical hypersensitivity after treatment with an HDAC6 inhibitor. Pointing to a specific role for δ opioid receptors (DORs), Oprd1 expression was decreased in DRG neurons following cisplatin administration, but normalized after treatment with an HDAC6 inhibitor. Mechanical hypersensitivity was temporarily reinstated in both sexes by a single injection of the DOR antagonist naltrindole. Consistently, HDAC6 inhibition failed to reverse cisplatin-induced hypersensitivity when DORs were genetically deleted from advillin+ neurons. Mechanical hypersensitivity was also temporarily reinstated in both sexes by a single injection of a neutralizing antibody against the DOR ligand met-enkephalin. In conclusion, we reveal that treatment with an HDAC6 inhibitor induces tonic enkephalin-DOR signaling in peripheral sensory neurons to suppress mechanical hypersensitivity. SIGNIFICANCE STATEMENT Over one-fourth of cancer survivors suffer from intractable painful chemotherapy-induced peripheral neuropathy (CIPN), which can last for months to years after treatment ends. HDAC6 inhibition is a novel strategy to reverse CIPN without negatively interfering with tumor growth, but the mechanisms responsible for persistent reversal are not well understood. We built on evidence that the endogenous opioid system contributes to the spontaneous, apparent resolution of pain caused by nerve damage or inflammation, referred to as latent sensitization. We show that blocking the δ opioid receptor or its ligand enkephalin unmasks CIPN in mice treated with an HDAC6 inhibitor (latent sensitization). Our work provides insight into the mechanisms by which treatment with an HDAC6 inhibitor apparently reverses CIPN.