Cynandione A attenuates neuropathic pain through p38β MAPK-mediated spinal microglial expression of β-endorphin

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%, ED5os of 14.9 p.g and 6.5 lig, respectively. Intrathecal injection of cynandione A significantly increased p-endorphin levels in spinal cords of neuropathic rats and its treatment concentration -dependently induced I3-endorphin expression in cultured primary microglia (but not in neurons or astrocytes), with EC50s of 38.8 and 20.0 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 (JNI() in primary microglial culture; however, cynandione A-stimulated beta-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 p380 but not p38ot using siRNA also completely blocked cynandione A-induced beta-endorphin expression in cultured microglial cells. Furthermore, cynandione A induced antiallodynia in neuropathy was totally inhibited by the microglial inhibitor minocycline, SB203580, anti-p-endorphin antibody, and-opioid receptor antagonist CTAP (but not the k-or delta opioid receptor antagonist). These results suggest that cynandione A attenuates neuropathic pain through upregulation of spinal microglial expression beta -endorphin via p38 beta MAPK activation. (C) 2017 Elsevier Inc. All rights reserved.