Calpain-2 Regulates TNF-α Expression Associated with Neuropathic Pain Following Motor Nerve Injury

• Published in: Neuroscience 2018-04, Vol.376, p.142-151
• Main Authors: Chen, Shao-Xia, Liao, Guang-Jie, Yao, Pei-Wen, Wang, Shao-Kun, Li, Yong-Yong, Zeng, Wei-an, Liu, Xian-Guo, Zang, Ying
• Format: Article
• Language: English
• Subjects: Animals; Calpain - administration & dosage; Calpain - antagonists & inhibitors; Calpain - metabolism; calpain-2 (CALP2); Disease Models, Animal; dorsal root ganglias (DRG); Functional Laterality; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; Gene Expression Regulation; Hyperalgesia - etiology; Hyperalgesia - metabolism; Hyperalgesia - pathology; L5 ventral root transection (L5-VRT); Lumbar Vertebrae; Male; Neuralgia - etiology; Neuralgia - metabolism; Neuralgia - pathology; Pain Threshold - physiology; Rats, Sprague-Dawley; spinal cord; Spinal Cord - metabolism; Spinal Cord - pathology; Spinal Nerve Roots - injuries; Spinal Nerve Roots - metabolism; Touch; Tumor Necrosis Factor-alpha - metabolism; tumor necrosis factor-α (TNF-α)
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2018.02.023

CALP2 regulates TNF-α expression and allodynia after motor nerve injury. L5-VRT leads to upregulation of CALP2 and TNF-α in bilateral DRGs and spinal cord, thus inducing bilateral allodynia. Pretreatment of calpain inhibitor MDL28170 significantly reduces CALP2 and TNF-α expression levels and relieves bilateral allodynia. Introducing rr-CALP2 to the surface of L5 DRG of uninjured rats results in TNF-α overexpression in bilateral DRGs and spinal cord, and induces pain hypersensitivity. [Display omitted] •Robust elevation of CALP2 and TNF-α in bilateral DRGs and spinal cord neurons following L5-VRT.•TNF-α is co-localized with Calpain-2.•CALP2 and TNF-α elevation by L5-VRT were inhibited by pretreatment with calpain inhibitor.•Administration of CALP2 to rats without nerve injury further supported CALP2 regulates TNF-α.•The linking of CALP2 and TNF-α provides a perspective for treating neuropathic pain. Both calpain-2 (CALP2) and tumor necrosis factor-α (TNF-α) contribute to persistent bilateral hypersensitivity in animals subjected to L5 ventral root transection (L5-VRT), a model of selective motor fiber injury without sensory nerve damage. However, specific upstream mechanisms regulating TNF-α overexpression and possible relationships linking CALP2 and TNF-α have not yet been investigated in this model. We examined changes in CALP2 and TNF-α protein levels and alterations in bilateral mechanical threshold within 24 h following L5-VRT model injury. We observed robust elevation of CALP2 and TNF-α in bilateral dorsal root ganglias (DRGs) and bilateral spinal cord neurons. CALP2 and TNF-α protein induction by L5-VRT were significantly inhibited by pretreatment using the calpain inhibitor MDL28170. Administration of CALP2 to rats without nerve injury further supported a role of CALP2 in the regulation of TNF-α expression. Although clinical trials of calpain inhibition therapy for alleviation of neuropathic pain induced by motor nerve injury have not yet shown success, our observations linking CALP2 and TNF-α provide a framework of a systems’ approach based perspective for treating neuropathic pain.