Bazan Hernan A, Giles Brian L, Bhattacharjee Surjyadipta, Edwards Scott, Bazan Nicolas G
Division of Vascular and Endovascular Surgery, Sutter Health, California Pacific Medical Center, San Francisco, CA 94109, USA.
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112, USA.
Neurobiol Pain. 2025 Jul 20;18:100192. doi: 10.1016/j.ynpai.2025.100192. eCollection 2025 Jul-Dec.
Acetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP's limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, from the periaqueductal gray (PAG) midbrain region, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund's adjuvant (CFA)-induced inflammatory pain against no treatment and vehicle controls. Our analysis revealed differential activity in three transcription factor families (SOX, SP/KLF, and AP-1) with cell-specific patterns and altered neuron-neuron interactions through neurexin-neuregulin signaling. SRP-001 and ApAP demonstrated similar genetic and epigenetic outcomes, indicating that SRP-001 is a favorable alternative due to its non-hepatotoxic properties while maintaining the same antinociceptive effects as ApAP.
对乙酰氨基酚（ApAP）被广泛用于疼痛管理，但过度使用或过量会导致肝毒性，使其成为全球急性肝衰竭的主要原因。由于其他非阿片类镇痛药如非甾体抗炎药（NSAIDs）具有肾毒性，因此迫切需要更安全的止痛药。我们已确定SRP-001是一种更安全、无肝毒性的新型镇痛药，它通过避免NAPQI的形成和保持肝紧密连接来克服ApAP的局限性。利用来自中脑导水管周围灰质（PAG）区域的RNA和ATAC测序联用技术，我们比较了在完全弗氏佐剂（CFA）诱导的炎性疼痛后，SRP-001和ApAP治疗与未治疗及溶剂对照相比的基因和表观遗传特征。我们的分析揭示了三个转录因子家族（SOX、SP/KLF和AP-1）的差异活性，具有细胞特异性模式，并通过神经纤毛蛋白-神经调节蛋白信号改变了神经元-神经元相互作用。SRP-001和ApAP表现出相似的基因和表观遗传结果，表明SRP-001因其无肝毒性特性，同时保持与ApAP相同的镇痛效果，是一种有利的替代品。
