title: Cynandione A attenuates neuropathic pain through p38β MAPK-mediated spinal microglial expression of β-endorphin.
abstract: Cynanchi Wilfordii Radix (baishouwu), a medicinal herb, has been widely used in Asia to treat a variety of diseases or illnesses. Cynandione A isolated from C. Wilfordii is the principle acetophenone and exhibits neuroprotective and anti-inflammatory activities. This study aims to evaluate the antihypersensitivity activities of cynandione A in neuropathy and explored its mechanisms of action. Intrathecal injection of cynandione A dose-dependently attenuated spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia, with maximal possible effects of 57% and 59%, ED50s of 14.9μg and 6.5μg, respectively. Intrathecal injection of cynandione A significantly increased β-endorphin levels in spinal cords of neuropathic rats and its treatment concentration-dependently induced β-endorphin expression in cultured primary microglia (but not in neurons or astrocytes), with EC50s of 38.8 and 20.0μM, respectively. Cynandione A also non-selectively upregulated phosphorylation of mitogen-activated protein kinases (MAPKs), including p38, extracellular signal regulated kinase (ERK1/2), and extracellular signal regulated kinase (JNK) in primary microglial culture; however, cynandione A-stimulated β-endorphin expression was completely inhibited by the specific p38 activation inhibitor SB203580, but not by the ERK1/2 or JNK activation inhibitors. Knockdown of spinal p38β but not p38α using siRNA also completely blocked cynandione A-induced β-endorphin expression in cultured microglial cells. Furthermore, cynandione A-induced antiallodynia in neuropathy was totally inhibited by the microglial inhibitor minocycline, SB203580, anti-β-endorphin antibody, and μ-opioid receptor antagonist CTAP (but not the κ- or δ-opioid receptor antagonist). These results suggest that cynandione A attenuates neuropathic pain through upregulation of spinal microglial expression β-endorphin via p38β MAPK activation.
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: windysalad@hotmail.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: nancylittle@163.com.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Mao
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: wuhaiyunsjtu@163.com.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: lh.tiger.9@gmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: sunny1991725@163.com.
authors.forename: Ming-Li
authors.initials: ML
authors.lastname: Sun
authors.affiliation: Shandong Analysis and Test Center, Shandong Academy of Sciences, 19 Keyuan Street, Jinan 250014, Shandong, China. Electronic address: wangx@sdas.org.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000700:Analgesics; D001713:Biphenyl Compounds; C403944:cynandione A; D001615:beta-Endorphin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cynandione A; Microglia; Neuropathic pain; p38β MAPK; β-Endorphin