我们曾报道切断腰5运动前根（L5-VRT）引起背根神经节内肿瘤坏死因子α（TNF-α）上调；后者通过促使钠通道过表达导致慢性痛产生。但L5-VRT上调TNF-α的机制尚不清楚。研究表明，核转录因子NF-κB参与TNF-α的基因调控；而钙依赖性蛋白酶calpain又可促使NF-κB活化入核。预实验显示腰5神经根局部敷予calpain诱导痛阈下降和TNF-α上调。我们推测,运动神经损伤激活的calpain可能通过NF-κB上调TNF-α，诱导慢性痛产生。本项目拟进一步明确： Calpain在运动神经损伤后慢性痛诱导和维持中的作用？ Calpain是否通过促使感觉传入异常兴奋、增强脊髓背角突触传递效率参与痛诱导？探讨L5-VRT 后由"Calpain→NF-κB→TNF-α→Calpain"环路介导的外周/中枢敏感化机制？本项目将揭示calpain在慢性痛中的作用及机制，为防治慢性痛提供新靶点。

Our previous work has shown that selective injury of motor fibers, but leaving sensory neurons intact by L5 ventral root transection (L5-VRT), which leads to neuropathic pain, up-regulates tumor necrosis factor-alpha (TNF-α) and TNF receptor 1 (TNFR1) in uninjured dorsal root ganglia (DRG) and that the increased TNF-α is responsible for the upregulation of voltage-gated sodium channels Nav1.3 and Nav1.8 in uninjured DRG neurons. However, what factors contribute to the upregulation of TNF-α in primary sensory afferents following motor fiber injury is still unknown. A large body of studies has demonstrated that the activation of nucleus factor-kappaB (NF-κB) is required for the development of neuropathic pain, which regulates the expression of TNF-α. Calpain is an ubiquitous calcium-sensitive protease, the activation of which may be an early event in a proteolytic cascade that is initiated by axonal injury and culminates with axonal degeneration. Several groups have shown that calpain can activate IκBα degradation and NF-κB translocation into the neucleus. In our preliminary experiment, administration of the recombinant rat m-calpain (rm-calpain) onto the surface of L5 spinal root induced the decrease of paw withdrawal threshold and up-regulates the expression of TNF-α protein in bilateral DRGs and spinal cord. Based on our present works, we will further investigate ① whether motor nerve injury by L5-VRT activates μ- and m-calpain in DRGs and spinal cord, and whether the intervention of calpain inhibits the induction of chronic pain? ② whether calpain is involved in the long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn,and whether calpain affects the neuronal action potential threshold and spinal NMDA/AMPA receptor current and dendritic morphosis? ③ whether the upregulation of TNF-α after L5-VRT was triggered by calpain via IκBα/ NF-κB pathway? The present project aims to reveal the roles and mechanisms of calpain in neuropathic pain, and to provide a new target for clinical therapy.