Neonatal vincristine administration modulates intrinsic neuronal excitability in the rat dorsal root ganglion and spinal dorsal horn during adolescence

摘要

Our recent work has shown that the early-life administration of vincristine (VNC), commonly used to treat pediatric cancers, evokes mechanical pain hypersensitivity in rats that emerges during adolescence and persists into adulthood. However, the underlying mechanisms remain unclear, as nothing is known about how neonatal VNC treatment influences peripheral and central nociceptive processing at the cellular level. Here, we used in vitro intracellular microelectrode and whole-cell patch-clamp recordings to evaluate the consequences of early-life VNC administration on the intrinsic membrane properties of adolescent dorsal root ganglion and spinal superficial dorsal horn neurons. The results demonstrate that VNC treatment increased the prevalence and rate of repetitive firing in both large- and medium-diameter sensory neurons, while reducing repetitive firing in small-diameter neurons, in comparison with vehicle-treated littermate controls. By contrast, passive membrane properties and peripheral conduction velocities were similar between experimental groups across all classes of primary afferents. Within the adolescent superficial dorsal horn, neonatal VNC exposure significantly enhanced the intrinsic membrane excitability of lamina I spinoparabrachial neurons, as evidenced by a decrease in rheobase and elevation of repetitive firing frequency compared with controls. Meanwhile, putative intemeurons within lamina I exhibited a reduction in repetitive action potential discharge after early-life chemotherapy. Collectively, these findings suggest that neonatal VNC treatment evokes cell type-specific changes in intrinsic excitability at multiple levels of the ascending pain pathway. Overall, this work lays an essential foundation for the future exploration of the ionic mechanisms that drive chemotherapy-induced chronic pain in children and adolescents.