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Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain
Science Immunology ( IF 17.6 ) Pub Date : 2024-08-23 , DOI: 10.1126/sciimmunol.adh0545
Philipp Starkl 1 , Gustav Jonsson 2, 3, 4 , Tyler Artner 1, 5 , Bruna Lenfers Turnes 6, 7 , Laura-Marie Gail 8, 9 , Tiago Oliveira 2, 3 , Aakanksha Jain 6, 7 , Nadine Serhan 10 , Karel Stejskal 3 , Karin Lakovits 1 , Anastasiya Hladik 1 , Meilin An 11 , Keith M Channon 12 , Hail Kim 13 , Thomas Köcher 14 , Wolfgang Weninger 8 , Georg Stary 8, 9 , Sylvia Knapp 1, 15 , Victoria Klang 16 , Nicolas Gaudenzio 10, 17 , Clifford J Woolf 6, 7 , Shweta Tikoo 8 , Rohit Jain 8 , Josef M Penninger 2, 3, 11, 18 , Shane J F Cronin 2, 3
Affiliation  

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1 , the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

中文翻译:


肥大细胞衍生的 BH4 和血清素是术后疼痛的关键介质



术后疼痛影响大多数大手术后的患者,并可能转变为慢性疼痛。当前治疗的相当大的副作用和有限的功效强调了对新的治疗选择的需要。我们观察到皮肤损伤后代谢物 BH4 和血清素的含量增加。肥大细胞是 Gch1 的主要术后来源,Gch1 是 BH4 合成中的限速酶,其本身是色氨酸羟化酶 (Tph1) 产生血清素的专性辅因子。缺乏肥大细胞或肥大细胞特异性 Gch1 或 Tph1 的小鼠表现出术后疼痛显着减轻。我们发现损伤诱导伤害性神经肽 P 物质、肥大细胞脱颗粒和颗粒神经共定位。 P 物质触发小鼠和人类肥大细胞中血清素的释放,而 P 物质受体阻断则显着改善疼痛过敏。我们的研究结果强调了神经免疫界面中肥大细胞的重要性以及 P 物质驱动的肥大细胞 BH4 和血清素产生作为术后疼痛治疗的治疗靶点的重要性。
更新日期:2024-08-23
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