Pasmay Andrea A, Pritha Ariana N, Carter Justin R, Jones Alissa, Fernandez-Oropeza Annette K, Sun Melody S, Jimenez Diane C, Murphy Minerva, Valenzuela C Fernando, Noor Shahani
Department of Neurosciences, University of New Mexico HSC, Reginald Heber Fitz Hall-145, MSC08 4740, Albuquerque, NM 87131, United States.
Department of Neurosciences, University of New Mexico HSC, Reginald Heber Fitz Hall-145, MSC08 4740, Albuquerque, NM 87131, United States.
Brain Behav Immun. 2025 Jul 6;129:736-756. doi: 10.1016/j.bbi.2025.06.041.
Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. While the immune mechanism(s) of PAE-induced immune dysfunction are poorly understood, prior studies implicated the involvement of Toll-like receptor 4 (TLR4) and the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasomes. Interestingly, emerging data suggest a surprising overlap of spinal glial proinflammatory activation via the TLR4-NLRP3-interleukin (IL)-1β axis due to opioid treatment in nerve-injured non-PAE rodents. Considering this preclinical evidence, we explored whether PAE poses a risk factor in creating proinflammatory immune bias consequent to opioid (morphine) exposure. We hypothesized that under nerve injury conditions, PAE may interact with morphine, promoting peripheral and CNS proinflammatory factors in a NLRP3-dependent manner. Using a minor nerve injury model in adult mice, we demonstrate that PAE prolongs the chronicity of ongoing allodynia in both sexes, with a more pronounced effect observed in male mice. Our study shows that PAE amplifies proinflammatory responses at the injury site and the spinal cord, driving morphine-prolonged allodynia through NLRP3 inflammasome activation. Furthermore, high mobility group box 1 (HMGB1), a well-established pain-promoting TLR4 agonist, is elevated in allodynic PAE mice. NLRP3 inhibitor, MCC950, effectively reverses morphine-induced allodynia and reduces Caspase-1 activity, IL-1β, and related proinflammatory factors. Although few sex-specific effects were observed, our data convincingly support that PAE and morphine interactions ultimately converge on NLRP3-driven mechanisms in both sexes. Together, this study suggests that PAE modulates later-life neuroimmune function and provides critical insights into immune regulators underlying PAE-induced biological vulnerability to pathological pain processing and adverse effects of opioids.
子宫内的不良状况可能会对神经免疫功能产生终身影响。我们之前的研究表明，产前酒精暴露（PAE）会增加外周坐骨神经损伤后的病理性疼痛敏感性（异常性疼痛）。虽然PAE诱导的免疫功能障碍的免疫机制尚不清楚，但先前的研究表明Toll样受体4（TLR4）和含核苷酸结合域、富含亮氨酸重复序列的家族、含pyrin结构域的3（NLRP3）炎性小体参与其中。有趣的是，新出现的数据表明，在神经损伤的非PAE啮齿动物中，由于阿片类药物治疗，通过TLR4-NLRP3-白细胞介素（IL）-1β轴，脊髓胶质细胞的促炎激活存在惊人的重叠。考虑到这一临床前证据，我们探讨了PAE是否是导致阿片类药物（吗啡）暴露后产生促炎免疫偏向的危险因素。我们假设，在神经损伤条件下，PAE可能与吗啡相互作用，以NLRP3依赖的方式促进外周和中枢神经系统促炎因子。使用成年小鼠的轻微神经损伤模型，我们证明PAE会延长两性持续异常性疼痛的慢性期，在雄性小鼠中观察到的效果更明显。我们的研究表明，PAE会放大损伤部位和脊髓的促炎反应，通过NLRP3炎性小体激活导致吗啡延长的异常性疼痛。此外，高迁移率族蛋白B1（HMGB1）是一种公认的促进疼痛的TLR4激动剂，在异常性疼痛的PAE小鼠中升高。NLRP3抑制剂MCC950可有效逆转吗啡诱导的异常性疼痛，并降低半胱天冬酶-1活性、IL-1β和相关促炎因子。虽然观察到的性别特异性效应很少，但我们的数据有力地支持了PAE和吗啡的相互作用最终在两性中都集中在NLRP3驱动的机制上。总之，这项研究表明PAE会调节后期生活中的神经免疫功能，并为PAE诱导的对病理性疼痛处理和阿片类药物不良反应的生物学易感性的免疫调节因子提供了关键见解。
