Intrathecal Injection of Dual Zipper Kinase shRNA Alleviating the Neuropathic Pain in a Chronic Constrictive Nerve Injury Model.

Meei-Ling Sheu,Chun-Jung Chen,Jason Sheehan,Chien-Yi Chiang,Hong-Lin Su,Hung-Chuan Pan

doi:10.3390/ijms19082421

Abstract

Dual leucine zipper kinase (DLK) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family mainly involved in neuronal degeneration. However, the role of DLK signaling in the neuropathic pain has not yet been fully determined. Chronic constrictive injury (CCI) was conducted by four 3-0 chromic gut ligatures loosely ligated around the sciatic nerve. Escalated DLK expression over the dorsal root ganglion was observed from one to four rings of CCI. Remarkable expression of DLK was observed in primary dorsal root ganglion cells culture subjected to electrical stimulation and attenuated by DLK short hairpin RNA (shRNA) treatment. Intrathecal injection of DLK shRNA attenuates the expression of DLK over the dorsal root ganglion and hippocampus neurons and increased the threshold of mechanical allodynia and decreased thermal hyperalgesia. In CatWalk gait analysis, significant decreases of print area, maximum contact maximum intensity, stand phase, single stance, and regular index by CCI were alleviated by the DLK shRNA administration. In conclusion, the expression of DLK was up-regulated in chronic constrictive injury and attenuated by the administration of DLK shRNA, which paralleled the improvement of neurobehavior of neuropathic pain. The modulation of DLK expression is a potential clinic treatment option for neuropathic pain.

Highlights

Neuropathic pain is well-known for a damage involved in the somatosensory system, and is usually defined as pain initiated or caused by a primary lesion or dysfunction of the nervous system [1,2]
Nerve injury and spinal cord damage induces an extreme activation of mitogen-activated protein kinase (MAPK) in glial cells of the spinal cord and on some occasions, peripheral nerve injury activates the downstream cascade of p38 and extracellular signal-regulated kinases (ERK) in spinal microglia [3,4,5,6]
This study showed that escalated expression of dual leucine zipper bearing kinase (DLK) in dorsal root ganglion and hippocampus neurons subjected to the severity of nerve constrictive injury, and the alleviation of neuroinflammation and improvement of neurobehavior were shown by the intrathecal injection of DLK ShRNA

Summary

Introduction

Neuropathic pain is well-known for a damage involved in the somatosensory system, and is usually defined as pain initiated or caused by a primary lesion or dysfunction of the nervous system [1,2]. A high proportion of the general population, up to 8%, will experience chronic pain associated with neuropathic features, which significantly affects their lives psychologically, physically, and socially. This pain usually poorly responds to traditional analgesics such as anti-inflammatory and opiate drugs [1]. As a mixed lineage kinase from the kinases of mitogen-activated protein kinase kinase kinases (MAP3K) for c-Jun N-terminal kinases (JNKs), dual leucine zipper bearing kinase (DLK) is worth noting [10,11,12]. Injury to the axon leads to activation of DLK downstream targets including mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) [16]. The modulation of nerve crush associated degeneration by DLK seems to be a potential role in the alleviation of neuropathic pain

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