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Neuropathic pain is one of the most common conditions requiring treatment worldwide. Salidroside (SAL), a phenylpropanoid glucoside extracted from Rhodiola, has been suggested to produce an analgesic effect in chronic pain. However, whether SAL could alleviate pain hypersensitivity after peripheral nerve injury and its mode of action remains unclear. Several studies suggest that activation of the spinal NOD-like receptor protein 3 (NLRP3) inflammasome and its related proteins contribute to neuropathic pain's pathogenesis. This study investigates the time course of activation of spinal NLRP3 inflammasome axis in the development of neuropathic pain and also whether SAL could be an effective treatment for this type of pain by modulating NLRP3 inflammasome. In the chronic constriction injury (CCI) mice model, spinal NLRP3 inflammasome-related proteins and TXNIP, the mediator of NLRP3, were upregulated from the 14th to the 28th day after injury. The TXNIP and NLRP3 inflammasome-related proteins were mainly present in neurons and microglial cells in the spinal dorsal horn after CCI. Intraperitoneal injection of SAL at 200 mg/kg for 14 consecutive days starting from the 7th day of CCI injury could ameliorate mechanical and thermal hypersensitivity in the CCI model. Moreover, SAL inhibited the activation of the TXNIP/NLRP3 inflammasome axis and mitigated the neuronal loss of spinal dorsal horn induced by nerve injury. These results indicate that SAL could produce analgesic and neuroprotective effects in the CCI model of neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: The nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in dorsal root ganglion (DRG) contributes to pain hypersensitivity in multiple neuropathic pain models, but the function of the NLRP3 in diabetic neuropathic pain (DNP) and the regulation mechanism are still largely unknown. Epigenetic regulation plays a vital role in the controlling of gene expression. Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a DNA demethylase that contributes to transcriptional activation. TET2 is also involved in high glucose (HG)-induced pathology. Methods: DNP was induced in mice via the intraperitoneal injection of streptozotocin (STZ) for five consecutive days and the mechanical threshold was evaluated in STZ-diabetic mice by using von Frey hairs. The expression level of the NLRP3 pathway and TET2 in DRG were determined through molecular biology experiments. The regulation of the NLRP3 pathway by TET2 was examined in in vitro and in vivo conditions. Results: In the present research, we first established the DNP model and found that NLRP3 pathway was activated in DRG. The treatment of NLRP3 inhibitor MCC950 alleviated the mechanical allodynia of DNP mice. Then we revealed that in STZ-diabetic mice DRG, the genomic DNA was demethylated, and the expression of DNA demethylase TET2 was increased evidently. Using RNA-sequencing analysis, we found that the expression of Txnip, a gene that encodes a thioredoxin-interacting protein (TXNIP) which mediates NLRP3 activation, was elevated in the DRG after STZ treatment. In addition, knocking down of TET2 expression in DRG using TET2-siRNA suppressed the mRNA expression of Txnip and subsequently inhibited the expression/activation of NLRP3 inflammasome in vitro and in vivo as well as relieved the pain sensitivity of DNP animals. Conclusion: The results suggested that the upregulation of the TXNIP/NLRP3 pathway by TET2 in DRG was involved in the pain hypersensitivity of the DNP model. [ABSTRACT FROM AUTHOR]

Reactive astrocytes play a complex role in multiple sclerosis, and the astrocytes reactivity is an important factor in the pathogenesis of pain. It is of great significance to explore the genesis and development mechanism of pain in the early stage of multiple sclerosis (MS) for early intervention of the disease. This study aims to explore astrocyte reactivity at different stages of the experimental autoimmune encephalomyelitis (EAE) model, a mouse model of MS, and the role of astrocytes in the pain in the early stage of the EAE. In this study, we demonstrated that spinal dorsal horn astrocytes were activated in the pre-clinical stage of EAE mice, and the inhibition of spinal cord astrocyte reactivity effectively alleviates pain symptoms in EAE mice. On the other hand, spinal cord microglia were not directly participated in the early EAE pain. Moreover, the ion channel LRRC8A mediated the reactivity of spinal dorsal horn astrocytes by regulating the STAT3 pathway, therefore playing a role in the early pain of EAE. • The astrocytes in spinal dorsal horn were activated at the early stage of EAE model. • The reactive astrocytes in spinal dorsal horn contributed to the pain at pre-onset stage of EAE model. • The LRRC8A channel was participated into the pain hypersensitivity of EAE model pain by regulating the astrocytes reactivity. [ABSTRACT FROM AUTHOR]