Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.

中文翻译：

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1-O-Acetylgeopyxin A 是一种真菌代谢物的衍生物，可阻断河豚毒素敏感的电压门控钠通道、钙通道和神经元兴奋性，从而抑制神经性疼痛。


慢性疼痛可能是由潜在疾病或病症、药物治疗、炎症或损伤引起的。经历这种疼痛的人数相当多，影响美国超过 5000 万成年人。大多数严重慢性疼痛患者的药物治疗包括加巴喷丁类药物、再摄取阻滞剂和阿片类药物。不幸的是，加巴喷丁类药物对该人群的三分之二无效，尽管阿片类药物最初可能有效，但长期使用会产生多种副作用。因此，非常需要开发新型非阿片类替代疗法来缓解慢性疼痛。为此，我们筛选了一个小型天然产物及其衍生物库，以寻找电压门控钙和钠通道的药理学抑制剂，这些通道由于它们在伤害感受途径中的重要作用而成为杰出的分子靶标。我们发现对映贝壳杉烷二萜类化合物的乙酰化衍生物 geopyxin A, 1-O-乙酰geopyxin A 可以阻断背根神经节 (DRG) 中的电压门控钙通道和河豚毒素敏感电压门控钠通道，但不能阻断河豚毒素抗性钠通道）神经元。与电压门控钠通道和钙通道的抑制一致，1-O-乙酰土霉素 A 降低了 DRG 神经元的动作电位放电频率并增加了放电阈值（流变碱）。最后，我们确定了 1-O-乙酰土霉素 A 在 HIV 诱导的感觉神经病临床前大鼠模型中逆转机械异常性疼痛的潜力。钠通道和钙通道的双重靶向可能会阻止伤害感受器的兴奋性和促伤害感受递质的释放。 未来的研究将利用土霉素的核心结构来生产抗伤害药物。