Research Paper|Volume 13, Issue 21|pp 24417—24431

RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling

Na He^1,², Yu-Juan Qu¹, Dan-Yang Li¹, Shou-Wei Yue¹

¹Rehabilitation Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
²Institute of Rehabilitation Engineering, University of Health and Rehabilitation Sciences, Qingdao, China

Received: July 2, 2021Accepted: October 26, 2021Published: November 12, 2021

https://doi.org/10.18632/aging.203691

Copyright: © 2021 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Neuroinflammation is a major contributor to neuropathic pain. Receptor interacting serine/threonine kinase 3 (RIP3) senses cellular stress, promotes inflammatory responses and activates c-Jun N-terminal kinase (JNK) signaling. Here, we assessed the involvement of RIP3-induced JNK signaling in chronic constriction injury (CCI)-induced neuropathic pain. We found that RIP3 inhibitors (GSK’872) and JNK inhibitors (SP600125) not only alleviated the radiant heat response and mechanical allodynia in CCI rats, but also reduced inflammatory factor levels in the lumbar spinal cord. CCI surgery induced RIP3 mRNA and protein expression in the spinal cord. GSK’872 treatment after CCI surgery reduced RIP3 and phosphorylated (p)-JNK expression in the spinal cord, whereas SP600125 treatment after CCI surgery had almost no effect on RIP3. Sinomenine treatment reduced RIP3, p-JNK and c-Fos levels in the spinal cords of CCI rats. These data demonstrated that RIP3 inhibition (particularly via sinomenine treatment) alleviates neuropathic pain by suppressing JNK signaling. RIP3 could thus be a new treatment target in patients with neuropathic pain.