Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile (Z.M., R.P.); Facultad de Ciencias Biológicas (Z.M., M.C.) and División de Anestesiología, Escuela de Medicina (M.C.), Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for the Study of Pain, Santiago, Chile (Z.M., M.C.); and Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile (R.P.).
Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile (Z.M., R.P.); Facultad de Ciencias Biológicas (Z.M., M.C.) and División de Anestesiología, Escuela de Medicina (M.C.), Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for the Study of Pain, Santiago, Chile (Z.M., M.C.); and Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile (R.P.)
Pharmacol Rev. 2023 Dec 15;76(1):7-36. doi: 10.1124/pharmrev.122.000674.
Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.
疼痛感知涉及外周伤害感受器神经的当前刺激以及随后脊髓中突触后兴奋性神经元的刺激。重要的是，在慢性疼痛中，外周伤害感受器和中枢神经系统中突触后神经元的神经活动都受到免疫系统产生的几种炎症介质的影响。越来越多的证据表明，共生微生物群通过直接作用于伤害感受器或通过调节免疫细胞的炎症活性，在调节疼痛感知方面发挥积极作用。这种共生关系是由可溶性细菌介质或细菌的内在结构成分介导的，这些成分作用于真核细胞，包括神经元、小胶质细胞、星形胶质细胞、巨噬细胞、T 细胞、肠嗜铬细胞和肠胶质细胞。分子机制涉及直接作用于神经元的细菌分子，影响其兴奋性，或间接作用于非神经元细胞，诱导促炎或抗炎介质的产生变化。重要的是，帕金森病是一种主要影响控制自主运动的多巴胺能神经元的神经退行性和炎症性疾病，不仅涉及运动能力下降，还涉及非运动症状，包括慢性疼痛。值得注意的是，最近的几项研究表明，帕金森病涉及肠道微生物群组成的失调。在这篇综述中，我们首先总结、整合和分类了微生物群介导的慢性疼痛调节中涉及的分子机制。其次，我们分析了与帕金森病相关的共生微生物群的变化，并提出了这些变化如何影响该病理学中慢性疼痛的发展。意义陈述：微生物群通过细菌信号的作用调节慢性疼痛，这些信号进入两个主要位置：外周伤害感受器和脊髓中的突触后兴奋性神经元。与帕金森病相关的失调显示出潜在加剧慢性疼痛的共生菌的代表性增加，以及对疼痛有有益影响的细菌水平降低。这篇综述鼓励进一步研究，以更好地了解细菌-细菌和细菌-宿主通信中涉及的信号，为开发具有治疗潜力的益生菌提供线索。
