Department of Clinical Laboratory, the First Hospital of Jilin University, Changchun, 130021, China.
Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA.
Mol Brain. 2020 May 11;13(1):73. doi: 10.1186/s13041-020-00616-2.
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.
慢性疼痛可能是潜在疾病或病症、医疗处理、炎症或损伤的结果。美国有大量的人经历这种类型的疼痛，影响了超过 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，加巴喷丁类药物在多达三分之二的人群中无效，虽然阿片类药物起初可能有效，但长期使用会引起多种副作用。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，我们在一个小型天然产物文库及其衍生物中进行筛选，寻找电压门控钙和钠通道的药理学抑制剂，这些通道是出色的分子靶点，因为它们在伤害性途径中起着重要作用。我们发现，贝壳杉烷二萜烯，即岩白菜素 A 的乙酰化衍生物 1-O-乙酰基岩白菜素 A，可阻断背根神经节 (DRG) 神经元中的电压门控钙和河豚毒素敏感型电压门控钠通道，但不能阻断河豚毒素抗性钠通道。与抑制电压门控钙和钠通道一致，1-O-乙酰基岩白菜素 A 降低了 DRG 神经元动作电位的发放频率，并增加了发放阈值（基强度）。最后，我们确定 1-O-乙酰基岩白菜素 A 有潜力逆转 HIV 诱导的感觉性神经病的临床前大鼠模型中的机械性痛觉过敏。同时靶向钠和钙通道可能会阻止伤害感受器的兴奋性和伤害性递质的释放。未来的研究将利用岩白菜素的核心结构来生成抗伤害性药物。
