Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement.
Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement.
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DOI：
10.1186/s13075-022-02975-8
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发表时间：
2022-12-23
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
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作者：
类风湿性关节炎患者通常患有关节炎性慢性疼痛。然而，由于对自身免疫性疾病的机制了解不完全，对关节炎疼痛的治疗并不令人满意。本文研究了天然类黄酮柚皮素（NAR）对胶原性关节炎（CIA）疼痛的镇痛作用及其机制。初免疫42 d后，每天1次注射NAR (i.p)，于第28天（末免疫21天，PID 21）和第42天（PID 35）处死大鼠。进一步研究NAR的炎症因子、中枢致敏指标、CRMP2磷酸化以及抗类风湿活性和镇痛作用。我们发现NAR降低了关节炎评分和足跖肿胀，以及机械和热痛。免疫荧光结果还显示NAR在第28天（PID 21）和第42天（PID 35）降低脊髓cFos、IBA-1和GFAP的表达呈剂量依赖性。NAR降低了脊髓背角CRMP2 S522的磷酸化和CDK5激酶的表达，但pCRMP2 Y479不变。此外，CRMP2与NEUN共定位，但不与IBA-1或GFAP共定位，表明神经CRMP2磷酸化参与了cia相关性疼痛。最后，CRMP2 S522磷酸化选择性抑制剂(S)-lacosamide也能减轻关节炎疼痛。综上所述，我们的研究结果表明，NAR减轻了CIA模型中的炎症和慢性疼痛，这可能与其抑制神经元CRMP2 S522磷酸化有关，可能减轻中枢致敏。我们的研究为NAR作为非阿片类药物依赖性镇痛在关节炎疼痛中的潜在应用提供了证据。在线版本包含补充材料，可在10.1186/s13075-022-02975-8获得。
Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain. The online version contains supplementary material available at 10.1186/s13075-022-02975-8.
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影响因子：
4.9
作者：
Lee YC;Cui J;Lu B;Frits ML;Iannaccone CK;Shadick NA;Weinblatt ME;Solomon DH
通讯作者：
Solomon DH
影响因子：
5
作者：
Boyden, Sean D.;Hossain, Imtiyaz N.;Lee, Yvonne C.
通讯作者：
Lee, Yvonne C.
DOI：
10.1007/978-1-4939-8802-0_1
发表时间：
2018-01-01
期刊：
RHEUMATOID ARTHRITIS
影响因子：
--
作者：
Miyoshi, Maya;Liu, Shuang
通讯作者：
Liu, Shuang
影响因子：
4.6
作者：
Conde, Tiago A.;Mendes, Luis;Duarte, Iola F.
通讯作者：
Duarte, Iola F.
影响因子：
7.7
作者：
Lawal, Maryam;Olotu, Fisayo A.;Soliman, Mahmoud E. S.
通讯作者：
Soliman, Mahmoud E. S.