口服黄芩素缓解疼痛和瘙痒：感觉神经元中Nav1.7的作用

Oral baicalein for relieving pain and itching: The role of Nav1.7 in sensory neurons

摘要:

摘 要 目的：探究黄芩素（baicalein，BAI）在神经病理性疼痛和急慢性瘙痒中的作用及潜在的调控机制。方法：通过分别构建脊神经结扎模型（Spinal Nerve Ligation，SNL）、化疗诱导的周围神经病变（Chemotherapy-Induced Peripheral Neuropathy，CIPN）引起的神经病理性疼痛动物模型与组胺（Histamine, His）、氯喹（Chloroquine, CQ）、白细胞介素-31（Interleukin-31, IL-31）、二苯环丙烯酮（Diphenylcyclopropenone，DCP）引起的急慢性瘙痒动物模型，并在造模过程中持续口服BAI。利用行为学测试观察口服BAI对小鼠的神经损伤性痛觉、组胺能急性瘙痒、非组胺能急性瘙痒和慢性瘙痒的影响。通过实时荧光定量PCR（Quantitative Real-Time Polymerase Chain Reaction，qPCR）检测化疗药紫杉醇（Paclitaxel，PTX）造模后电压门控钠离子通道1.7型α亚基（Sodium channel protein type 9 subunit alpha，Nav1.7/SCN9A）在背根神经节（Dorsal root ganglion，DRG）中的表达变化；通过蛋白免疫印迹（Western Blotting，WB）检测PTX造模后Nav1.7在DRG中的表达变化；免疫荧光（Immunofluorescence, IF）检测PTX造模后Nav1.7在DRG中的表达变化。结果：口服BAI可以广泛的抑制SNL或PTX引起的神经病理性疼痛、组胺引起的组胺能急性瘙痒、CQ及IL-31引起的非组胺能急性瘙痒和DCP引起的慢性瘙痒，并且显著的下调PTX模型小鼠DRG中Nav1.7的表达。结论：口服BAI可以广泛的抑制小鼠的神经病理性疼痛和急慢性瘙痒，并且显著下调PTX模型小鼠DRG中Nav1.7的表达。

Abstract:

Abstract: Objective: To elucidate the therapeutic potential and underlying regulatory mechanisms of baicalein (BAI) in neuropathic pain and both histaminergic and non-histaminergic acute/chronic pruritus. Methods: We employed multiple well-established murine models: spinal nerve ligation (SNL) and paclitaxel-induced chemotherapy-related peripheral neuropathy (CIPN) for neuropathic pain; and histamine (His), chloroquine (CQ), interleukin-31 (IL-31), and diphenylcyclopropenone (DCP) for acute or chronic pruritus induction. BAI was administered orally throughout the modeling period. Behavioral assessments were conducted to evaluate the effects of BAI on mechanical allodynia (neuropathic pain), histamine-induced acute itch, and non-histaminergic acute itch (CQ- and IL-31-induced) as well as DCP-induced chronic itch. To investigate molecular mechanisms, Quantitative real-time polymerase chain reaction (qPCR), Western blotting (WB), and immunofluorescence (IF) were performed in parallel to quantify Nav1.7 (voltage-gated sodium channel 1.7 α-subunit, SCN9A) expression levels in dorsal root ganglia (DRG) following paclitaxel (PTX) treatment. Results: Chronic oral administration of BAI significantly downregulated Nav1.7 mRNA and protein expression in DRG neurons of PTX-treated mice. Concurrently, BAI markedly attenuated neuropathic pain in SNL and PTX models, suppressed histamine-induced acute pruritus, inhibited non-histaminergic acute pruritus elicited by CQ and IL-31, and alleviated DCP-induced chronic pruritus. Conclusion: BAI exerts broad-spectrum antinociceptive and antipruritic effects in preclinical models, at least partly through transcriptional and translational suppression of Nav1.7 in sensory neurons. These findings support Nav1.7 as a key mechanistic target and highlight BAI’s translational promise for treating refractory neuropathic pain and diverse forms of pruritus.