Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement

Jiang, Yue-Peng1; Wang, Song1; Lai, Wei-Dong1; Wu, Xue-Qing1; Jin, Yan1; Xu, Zheng-Hao1; Moutal, Aubin2; Khanna, Rajesh3,4; Park, Ki Duk5; Shan, Zhi-Ming6; Wen, Cheng-Ping1; Yu, Jie1

2022-12-23

10.1186/s13075-022-02975-8

Arthritis Research and Therapy   Impact Factor & Quartile

1478-6354

1478-6362

Background: 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.Methods: 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.Results: 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.Conclusions: 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.

Rheumatoid arthritis Chronic pain Central sensitization CRMP2 Naringenin

SCI

English

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Zhejiang Provincial Natural Science Foundation of China["81971052","82204649","82001188"] ; Foundation of Zhejiang Chinese Medical University[LY22H280008] ; National Key Research and Development Program of China["Q2019Y02","2022JKZKTS04"] ; [2018YFC1705501]

Rheumatology

Rheumatology

WOS:000904715700001

BMC

Web of Science

1.Zhejiang Chinese Med Univ, Coll Basic Med Sci, Coll Pharmaceut Sci, Key Lab Neuropharmacol & Translat Med Zhejiang Pr, Hangzhou 310058, Peoples R China
2.St Louis Univ, Sch Med, Dept Pharmacol & Physiol, St Louis, MO 63104 USA
3.NYU, Coll Dent, Dept Mol Pathobiol, New York, NY 10010 USA
4.NYU, NYU Pain Res Ctr, New York, NY 10010 USA
5.Korea Inst Sci & Technol, Seoul, South Korea
6.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Dept Anesthesiol,Clin Med Coll, Shenzhen 518020, Peoples R China

Jiang, Yue-Peng,Wang, Song,Lai, Wei-Dong,et al. Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement[J]. Arthritis Research and Therapy,2022,24(1).

Jiang, Yue-Peng.,Wang, Song.,Lai, Wei-Dong.,Wu, Xue-Qing.,Jin, Yan.,...&Yu, Jie.(2022).Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement.Arthritis Research and Therapy,24(1).

Jiang, Yue-Peng,et al."Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement".Arthritis Research and Therapy 24.1(2022).