Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Anesthesiology, Women and Children's Hospital of Ningbo University, Ningbo City, Zhejiang, China.
Department of Diving and Hyperbaric Medicine, Chinese People's Liberation Army Naval Medical Center, Shanghai, PR China.
J Pain. 2024 Nov;25(11):104623. doi: 10.1016/j.jpain.2024.104623. Epub 2024 Jul 11.
Chronic postsurgical pain (CPSP) affects postoperative rehabilitation and quality of life in patients, but its mechanisms are still poorly understood. Hyperbaric oxygen (HBO) attenuates neuropathic pain in animal and human studies, but its efficacy for CPSP treatment and its underlying mechanism have not been elucidated. This study aimed to investigate the analgesic effect of HBO in a CPSP rat model and the role of spinal cord adenosine circulation in HBO-induced analgesia. A skin/muscle incision and retraction (SMIR) rat model was used to mimic CPSP, and HBO treatment (2.5 atmospheric absolute, 60 minutes) was administered once daily for 5 consecutive days beginning 3 days after surgery. The role of spinal cord adenosine circulation in HBO-induced analgesia was investigated using β-methylene ADP (a CD73 inhibitor), 8-cyclopentyl-1,3-dipropylxanthine (an A1R antagonist), or an intrathecal injection of adenosine. The mechanical paw withdrawal threshold was determined at different timepoints before and after surgery. The spinal cord adenosine and adenosine triphosphate (ATP) contents were analyzed using high-performance liquid chromatography, and the spinal cord expression of adenosine-1 receptor (A1R), extracellular 5'-nucleotidase (CD73), and adenosine kinase (ADK) was examined by Western blotting and immunofluorescence staining. The results showed that the mechanical paw withdrawal threshold of the ipsilateral hind paw and the adenosine content decreased, and the spinal cord expression of A1R, CD73, and ADK and ATP content increased within 14 days after surgery. HBO treatment alleviated mechanical allodynia, reduced ATP content, and increased adenosine content by activating CD73 but downregulated the spinal cord expression of A1R, CD73, and ADK. Intrathecal adenosine alleviated mechanical allodynia after SMIR and downregulated the spinal cord expression of A1R and CD73, and intrathecal β-methylene ADP or 8-cyclopentyl-1,3-dipropylxanthine attenuated the analgesic effect of HBO treatment on SMIR-induced CPSP. PERSPECTIVE: Spinal cord adenosine is involved in the occurrence and development of CPSP, and HBO treatment alleviates CPSP by regulating adenosine production/metabolism in the spinal cord. Thus, HBO may be employed for the treatment of CPSP with favorable efficacy.
慢性术后疼痛（CPSP）影响患者术后康复和生活质量，但其机制仍知之甚少。高压氧（HBO）在动物和人类研究中减轻神经性疼痛，但 HBO 治疗 CPSP 的疗效及其潜在机制尚未阐明。本研究旨在探讨 HBO 在 CPSP 大鼠模型中的镇痛作用以及脊髓腺苷循环在 HBO 诱导的镇痛中的作用。采用皮肤/肌肉切开和牵拉（SMIR）大鼠模型模拟 CPSP，术后 3 天开始每天接受 1 次 HBO 治疗（2.5 绝对大气压，60 分钟），连续 5 天。使用β-亚甲基 ADP（CD73 抑制剂）、8-环戊基-1,3-二丙基黄嘌呤（A1R 拮抗剂）或鞘内注射腺苷来研究脊髓腺苷循环在 HBO 诱导的镇痛中的作用。在手术前后的不同时间点测定机械性爪回缩阈值。采用高效液相色谱法分析脊髓腺苷和三磷酸腺苷（ATP）含量，采用 Western blot 和免疫荧光染色法检测脊髓腺苷 A1 受体（A1R）、细胞外 5′-核苷酸酶（CD73）和腺苷激酶（ADK）的表达。结果显示，术后 14 天内，同侧后爪机械性爪回缩阈值降低，脊髓 A1R、CD73 和 ADK 表达及 ATP 含量增加。HBO 治疗通过激活 CD73 减轻机械性痛觉过敏，降低 ATP 含量，增加腺苷含量，但下调脊髓 A1R、CD73 和 ADK 表达。鞘内注射腺苷减轻 SMIR 后的机械性痛觉过敏，并下调脊髓 A1R 和 CD73 的表达，鞘内注射β-亚甲基 ADP 或 8-环戊基-1,3-二丙基黄嘌呤可减弱 HBO 治疗对 SMIR 诱导的 CPSP 的镇痛作用。展望：脊髓腺苷参与 CPSP 的发生发展，HBO 治疗通过调节脊髓腺苷的产生/代谢缓解 CPSP。因此，HBO 可能用于 CPSP 的治疗，疗效良好。
