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Early CALP 2 expression and microglial activation are potential inducers of spinal IL ‐6 up‐regulation and bilateral pain following motor nerve injury
Author(s) -
Chen ShaoXia,
Wang ShaoKun,
Yao PeiWen,
Liao GuangJie,
Na XiaoDong,
Li YongYong,
Zeng Weian,
Liu XianGuo,
Zang Ying
Publication year - 2018
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14317
Subject(s) - spinal cord , astrocyte , microglia , lumbar spinal cord , medicine , glial fibrillary acidic protein , neuropathic pain , nerve injury , anesthesia , allodynia , pathology , anatomy , endocrinology , nociception , hyperalgesia , immunohistochemistry , central nervous system , inflammation , receptor , psychiatry
Previous work from our laboratory showed that motor nerve injury by lumbar 5 ventral root transection (L5‐ VRT ) led to interleukin‐6 ( IL ‐6) over‐expression in bilateral spinal cord, and that intrathecal administration of IL ‐6 neutralizing antibody delayed the induction of mechanical allodynia in bilateral hind paws. However, early events and upstream mechanisms underlying spinal IL ‐6 expression following L5‐ VRT require elucidation. The model of L5‐ VRT was used to induce neuropathic pain, which was assessed with von Frey hairs and the plantar tester in adult male Sprague–Dawley rats. Calpain‐2 ( CALP 2, a calcium‐dependent protease) knockdown or over‐expression and microglia depletion were conducted intrathecally. Western blots and immunohistochemistry were performed to explore the possible mechanisms. Here, we provide the first evidence that both IL ‐6 and CALP 2 levels are increased in lumbar spinal cord within 30 min following L5‐ VRT . IL ‐6 and CALP 2 co‐localized in both spinal dorsal horn ( SDH ) and spinal ventral horn. Post‐operative ( PO ) increase in CALP 2 in ipsilateral SDH was evident at 10 min PO , preceding increased IL ‐6 at 20 min PO . Knockdown of spinal CALP 2 by intrathecal CALP 2‐sh RNA administration prevented VRT ‐induced IL ‐6 overproduction in ipsilateral spinal cord and alleviated bilateral mechanical allodynia. Spinal microglia activation also played a role in early IL ‐6 up‐regulation. Macrophage/microglia markers ED 1/Iba1 were increased at 30 min PO , while glial fibrillary acidic protein (astrocyte) and CNP ase (oligodendrocyte) markers were not. Increased Iba1 was detected as early as 20 min PO and peaked at 3 days. Morphology changed from a small soma with fine processes in resting cells to an activated ameboid shape. Depletion of microglia using Mac‐1‐saporin partially prevented IL ‐6 up‐regulation and attenuated VRT ‐induced bilateral mechanical allodynia. Taken together, our findings provide evidence that increased spinal cord CALP 2 and microglia cell activation may have early causative roles in IL ‐6 over‐expression following motor nerve injury. Agents that inhibit CALP 2 and/or microglia activation may therefore prove valuable for treating neuropathic pain.