Jun N-terminal kinase's role in neuropathic pain: C-fiber remodeling and growth-associated protein-43 phosphorylation

Peripheral nerve injury (PNI) often cause neuropathic pain and induces morphological changes in C-fiber terminals. Concurrently, PNI increased growth-associated protein-43 (GAP-43) levels and activated JNK in the injured dorsal root ganglion. A previous study demonstrated that JNK phosphorylates GAP-43 at S96 in growth cones, which are often considered a model for axon elongation.

The aim of this study was to investigate whether PNI-induced JNK is involved in the phosphorylation of GAP-43 and in the morphological changes of injured C-fiber terminal in dorsal horn.

In this study, we used a rat model of neuropathic pain to examine the expression of phosphorylated GAP-43 at Ser96 (pGAP-43) and to confirm the phosphorylation of JNK (pJNK). Furthermore, we investigated the localization of pGAP-43-positive terminals in the dorsal horn, specifically focusing on their coexpression with L1-CAM-labeled axonal varicosities. We chronically administered a JNK inhibitor intrathecally and assessed its effects on neuropathic pain behavior, expression of pGAP-43, and on injury-induced hypertrophy of L1-CAM-labeled varicosities in the dorsal horn.

PNI significantly increased pGAP-43 and pJNK in largely overlapping dorsal root ganglion neurons. In the dorsal horn ipsilateral to the injury, pGAP-43-positive terminals colocalized with L1-CAM-labeled axonal varicosities in laminae I-II. Chronic intrathecal JNK inhibition alleviated neuropathic pain and reduced pGAP-43 immunoreactivity in axon terminals, also preventing injury-induced hypertrophy of L1-CAM-labeled varicosities in the dorsal horn.