Cytochrome P45026A1 Contributes to the Maintenance of Neuropathic Pain  

作　　者：De-Li Cao Ling-Jie Ma Bao-Chun Jiang Qiang Gu Yong-Jing Gao 

机构地区：[1]Institute of Pain Medicine and Special Environmental Medicine,Co-innovation Center of Neuroregeneration,Nantong University,Nantong,226019,China [2]Nantong University Medical School,Nantong,226001,China [3]Department of Pain Management,The Affiliated Hospital of Nantong University,Nantong,226001,China

出　　处：《Neuroscience Bulletin》2024年第3期293-309,共17页神经科学通报（英文版）

基　　金：supported by STI2030-Major Projects(2022ZD0204700);the National Natural Science Foundation of China(32030048,31700899,and 32200817);the Graduate Student Scientific Research Innovation Projects of Jiangsu Province(KYCX18-2397);the Startup Foundation for Doctors of the Affiliated Hospital of Nantong University(Tdb1906).

摘　　要：The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative metabolism of retinoic acid(RA),the active metabolite of vitamin A.Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation(SNL).CYP26A1 was mainly expressed in spinal neurons and astrocytes.HPLC analysis displayed that the content of all-trans-RA(at-RA),the substrate of CYP26A1,was reduced in the spinal cord on day 7 after SNL.Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain.Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine(IL-10)production.The RA receptors RARα,RXRβ,and RXRγwere expressed in spinal neurons and glial cells.The promoter of Il-10 has several binding sites for RA receptors,and at-RA directly increased Il-10 mRNA expression in vitro.Finally,intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia.Collectively,the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation.CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.

关 键 词：CYP26A1 MICROGLIA ASTROCYTES ERK P38 IL-10 Neuropathic pain 

分 类 号：R741[医药卫生—神经病学与精神病学]