We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1β content of MPs increases 68-fold. IL-1β antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be are required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.

中文翻译：

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血源性和脑源性微粒在吗啡诱导的抗伤害耐受中的作用


我们假设给小鼠注射吗啡会导致微粒（MP）升高。重复给药以诱导抗伤害耐受性，可使血源性 MP 增加 8 倍，在引流脑淋巴管的颈深淋巴结中增加 10 倍。 MP 表达细胞特有的蛋白质，包括中性粒细胞、小胶质细胞、星形胶质细胞、神经元和少突胶质细胞。 MPs 中的白介素 (IL)-1β 含量增加了 68 倍。 IL-1β 拮抗剂给药可减少血源性和颈部淋巴结 MP，并消除耐受诱导。静脉注射聚乙二醇端聚物 B（一种裂解 MP 的表面活性剂）和腹腔注射甲基纳曲酮也能抑制 MP 升高和耐受性。重要的是，中性粒细胞减少症小鼠不会产生抗伤害耐受性、血源性或颈淋巴结 MP 升高。吗啡激活小胶质细胞的免疫组织化学证据与 MP 反应模式无关。中性粒细胞衍生的 MP 似乎是吗啡诱导的抗伤害耐受性所必需的。此外，接受阿片类药物使用障碍治疗的患者与耐受小鼠表现出相似的 MP 升高。