Xu Chu, Wu Jian-Hong, Yu Hui, Liu Yun-Xin, Zou Jian-Jun, Li Jun
Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
The Affiliated Mental Health Center of Jiangnan University, Wuxi Central Rehabilitation Hospital, Wuxi, China.
Neuropharmacology. 2025 May 15;269:110317. doi: 10.1016/j.neuropharm.2025.110317. Epub 2025 Jan 28.
Loss of GABAergic inhibition in the spinal dorsal horn (SDH) is implicated in central sensitization and chronic pain. Both agonists and positive allosteric modulators (PAMs) of GABAA receptor are found to be effective in the management of chronic pain. In addition to benzodiazepines, neuroactive steroids (NASs) also act as PAMs through binding to unique sites of GABAA receptors. Thus, it is worth investigating whether these NASs can attenuate chronic pain. This study tested the antinociceptive properties of two novel NAS PAMs, ganaxolone and zuranolone, in segmental spinal nerve ligation (SNL)-induced neuropathic pain and complete Freund's adjuvant (CFA)-induced inflammation pain models. Spinally administered ganaxolone and zuranolone both exhibited dose-dependent analgesic effects but with quite different durations. This antinociceptive effect might be generated from elevated GABAergic inhibition, as the PAMs both enhanced GABA-evoked currents in SDH neurons, and the K-Cl cotransporter isoform 2 (KCC2) antagonist reversed the analgesic effect of the PAMs. Different from ganaxolone, zuranolone produced a durable increase in the surface expression of GABAA receptors and of the amplitude of spontaneous inhibitory currents, which may contribute to the long-lasting analgesic effect. Furthermore, the PAMs alleviated SNL-induced mechanical allodynia synergistically with diazepam or GABAA receptor activator muscimol at inactive doses, consistent with the non-competitive activity and distinct binding sites from benzodiazepines. In summary, our findings suggest that NASs may not only acutely modulate GABA receptor activity but also induce sustained metabotropic effects on GABAA receptors and thus exert long-lasting antinociceptive effects.
脊髓背角（SDH）中γ-氨基丁酸能抑制作用的丧失与中枢敏化和慢性疼痛有关。γ-氨基丁酸A受体（GABAA受体）的激动剂和正变构调节剂（PAM）均被发现对慢性疼痛的治疗有效。除了苯二氮䓬类药物外，神经活性甾体（NAS）也通过与GABAA受体的独特位点结合而发挥PAM的作用。因此，研究这些NAS是否能减轻慢性疼痛是值得的。本研究在节段性脊神经结扎（SNL）诱导的神经性疼痛和完全弗氏佐剂（CFA）诱导的炎症性疼痛模型中，测试了两种新型NAS PAM——加奈索酮和左洛诺酮的镇痛特性。经脊髓给予加奈索酮和左洛诺酮均表现出剂量依赖性镇痛作用，但持续时间差异较大。这种镇痛作用可能是由增强的γ-氨基丁酸能抑制作用产生的，因为这两种PAM均增强了SDH神经元中γ-氨基丁酸诱发的电流，并且钾-氯共转运体同工型2（KCC2）拮抗剂可逆转PAM的镇痛作用。与加奈索酮不同，左洛诺酮使GABAA受体的表面表达和自发抑制性电流的幅度产生持久增加，这可能有助于产生持久的镇痛作用。此外，这些PAM与非活性剂量的地西泮或GABAA受体激动剂蝇蕈醇协同减轻SNL诱导的机械性异常性疼痛，这与它们的非竞争性活性以及与苯二氮䓬类药物不同的结合位点一致。总之，我们的研究结果表明，NAS不仅可以急性调节GABA受体活性，还可以对GABAA受体产生持续的代谢型效应，从而发挥持久的镇痛作用。
