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.
Highlights
Lesions of the nervous system can lead to neuropathic pain (NP), a severe disease in which generally harmless stimuli induce hyperalgesia and spontaneous pain
To assess the involvement of RIP3 and Jun N-terminal kinase (JNK) in CCIinduced NP, we randomly divided rats into four groups: rats subjected to a sham constriction injury (CCI) operation; CCI rats injected with saline; CCI rats injected with the RIP3 inhibitor GSK’872; and CCI rats injected with the JNK inhibitor SP600125
Pain behavior was monitored at different stages (1 day before CCI, 3 days after CCI, 7 days after CCI and 14 days after CCI) based on the paw withdrawal latency (PWL) in response to radiant heat and the paw withdrawal threshold (PWT) in response to mechanical allodynia
Summary
Lesions of the nervous system can lead to neuropathic pain (NP), a severe disease in which generally harmless stimuli induce hyperalgesia and spontaneous pain. NP can persist for months to years [1,2,3], causing considerable suffering to the affected patients and placing a substantial economic burden on individuals and countries [4, 5] Analgesics such as tricyclic anti-depressants, nonsteroidal anti-inflammatory drugs and opioids relieve symptoms by inhibiting neuronal activity, but their efficacy in hampering the progression of NP is not satisfactory [6,7,8]. Bennett and Xie proposed that chronic constriction injury (CCI) of the sciatic nerve could be used as a model of NP [20] By applying this model, researchers have discovered various molecules that contribute to NP [21], including members of the mitogen-activated protein kinase (MAPK) pathway. We first assessed the effects of RIP3 on the JNK signaling pathway in CCI-induced NP, and investigated the influence of sinomenine on RIP3 in NP
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