AUTHOR=Zhang Linlin , Li Nan , Zhang Haoyue , Wang Yigang , Gao Tianyu , Zhao Yuying , Wang Guolin , Yu Yonghao , Wang Chunyan , Li Yize 

TITLE=Artesunate Therapy Alleviates Fracture-Associated Chronic Pain After Orthopedic Surgery by Suppressing CCL21-Dependent TREM2/DAP12 Inflammatory Signaling in Mice

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.894963

DOI=10.3389/fphar.2022.894963

ISSN=1663-9812

ABSTRACT=Chronic pain after bone fracture and orthopedic surgery is often refractory to most analgesics currently in use, thus emphasizing the urgent need for improved therapeutic medications. Chemokines-dependent neuroinflammation is critical for excitatory synaptic plasticity and central nociception sensitization. Recent literatures have focused on the inhibition of inflammatory responses by artesunate, the 1st anti-malaria drug extracted from artemisinin. This present study investigated the analgesic effects and potential targets of artesunate in a mouse model of chronic pain induced by tibial fracture and orthopedic surgery. Three injections of artesunate were intrathecally administered on a daily basis from days 4 to 6 after fracture. We reported that repetitive exposure to artesunate (10 and 100μg but not 1μg) dose-dependently prevented fracture-induced mechanical and cold allodynia. Moreover, single intrathecal injection of artesunate (100μg) alleviated the established chronic pain on days 14 after fracture surgery. Intraperitoneal artesunate (10 and 50 mg kg−1) therapy was effective against chronic fracture pain. Intriguingly, artesunate inhibited the up-regulation of spinal chemokine CCL21, triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12) expressions and microglia activation in fracture mice. Furthermore, spinal CCL21 neutralization attenuated the severity of fracture-associated post-surgical pain. Exogenous CCL21-induced acute inflammatory pain was impaired by artesunate therapy. Additionally, pharmacological blockage of TREM2 reduced recombinant CCL21-elicited behavioral hypernociception. Our present findings demonstrate that artesunate therapy reduces the initiation and maintenance of fracture-associated chronic postoperative pain by inhibiting CCL21-dependent TREM2/DAP12 inflammatory signaling and microglia activation, thus suggesting that artesunate could emerge as a therapeutic strategy for fracture pain management.