Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA; Anesthesiology Service, Durham Veterans Affairs Health Care System, Durham, NC 27705, USA.
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Brain Behav Immun. 2023 Jul;111:298-311. doi: 10.1016/j.bbi.2023.04.013. Epub 2023 May 5.
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-β1, and resolvins D1/D2. Intrathecal injection of anti-TGF-β1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.
化疗引起的周围神经病（CIPN）是癌症化疗最常见的神经系统并发症，且其治疗选择有限。自体条件血清（ACS）是一种有效的生物疗法，通过关节内注射用于治疗骨关节炎患者。然而，ACS 尚未在治疗 CIPN 等周围神经病变方面进行系统测试。人们普遍认为，这种生物疗法的镇痛作用源自抗炎细胞因子和生长因子浓度的增加。在这里，我们报告单次鞘内注射人条件血清（hCS）可在小鼠中产生持久的紫杉醇化疗引起的神经性疼痛（机械性痛觉过敏）抑制作用，而不会引起运动障碍。引人注目的是，与非条件人血清（hNCS）相比，我们实验中的 hCS 镇痛作用甚至在治疗 8 周后仍能维持。此外，hCS 转移引起的小鼠疼痛缓解可通过大鼠或小鼠 CS 转移至雌雄小鼠中完全重现，表明具有跨物种和跨性别作用。从机制上讲，CS 治疗阻断了脊髓中化疗引起的神经胶质反应并改善了神经传导。与 NCS 相比，CS 中含有更高浓度的抗炎和促解决介质，包括 IL-1Ra、TIMP-1、TGF-β1 和 resolvins D1/D2。鞘内注射抗 TGF-β1 和抗 Il-1Ra 抗体可短暂逆转 CS 的镇痛作用。纳米颗粒跟踪分析显示，大鼠条件血清中含有比 NCS 更多的外泌体。重要的是，通过高速离心去除外泌体大大降低了 CS 产生的疼痛缓解作用，这表明小囊泡（外泌体）在 CS 的有益作用中具有关键作用。总之，我们的研究结果表明，鞘内 CS 通过小囊泡/外泌体和神经免疫/神经胶质调节的组合产生了显著的神经病理性疼痛缓解作用。
