Abstract
Neuropathic pain (NP) caused by nerve injuries continues to be an intractable challenge due to inadequate therapeutic strategies. Recent study demonstrated glia-induced neuro-inflammation in the spinal cord, especially the activation of astrocytes, plays an essential role in the development of NP, which opens new avenues for NP treatment. In this study, we explored the anti-hyperalgesia properties of Wu-tou decoction (WTD) and showed that WTD potently attenuates mechanical allodynia and heat hyperalgesia in lumbar 5 (L5) spinal nerve ligation (SNL)-induced NP without noticeable side effect or affecting basal pain perception of mice. Mechanistically, initial targets screening tests indicated WTD's analgesic action may be centrally mediated within the spinal cord, which further verified by its inhibitory actions on glia-releasing factors of IL-1β, CCL2 and CXCL1. Meanwhile, WTD significantly reduced spinal IL-1R1, TRAF6 expressions, p-JNK levels, and number of GFAP/IL-1R1, GFAP/TRAF6, GFAP/p-JNK positive astrocytes in the superficial lamina of spinal cord. Additionally, co-administration of IL-1Ra increased the anti-hyperalgesia effects of WTD and further decreased CCL2 and CXCL1 expressions, while no synergistic effects were detected when TRAF6 or JNK inhibitors were co-administrated with WTD. Thus, our data suggested that the effective inhibition of spinal astrocytic IL-1R1/TRAF6/JNK signaling (especially IL-1R1) contributes, at least in part, to WTD's anti-hyperalgesia action. It also indicates that WTD might be a promising candidate for the treatments of chronic pain, especially under NP-related neurological disorders.
Highlights
Neuropathic pain (NP) resulting from nerve damage is a devastating disease which mainly characterized by mechanical allodynia and thermal hyperalgesia [1,2,3]
Microglia produces multiple inflammatory mediators such as IL-1β and TNF-α, which mediate signaling from receptor super families, such as tumor necrosis factor receptor (TNFR) and interleukin-1 receptor (IL1R) by increasing TNF receptor associated factor 6 (TRAF6) expression [17,18,19], subsequently activate c-Jun N-terminal Kinase (JNK) and induce the production of chemokine such as C–C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 1 (CXCL1) in astrocytes that are implicated in pain sensitization [20, 21]
Our findings demonstrated that Wu-tou decoction (WTD) significantly attenuates spinal nerve ligation (SNL)-induced mechanical allodynia and heat hyperalgesia of mice possibly through inhibition of astrocytic IL-1R1/TRAF6/JNK signaling, and the effective inhibition of IL-1R1 maybe the key link that contributes to WTD analgesic action
Summary
Neuropathic pain (NP) resulting from nerve damage is a devastating disease which mainly characterized by mechanical allodynia and thermal hyperalgesia [1,2,3]. This excruciating conditions create considerable suffering for people affected, and bring extreme economic burden for the individual and for the community [4, 5]. Targeting glia-induced excessive neuroinflammation offers new therapeutic opportunities for NPrelated neurological disorders [2, 12,13,14]
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