AUTHOR=Han Qiao-Qiao , Yin Min , Wang Zi-Ying , Liu Hao , Ao Jun-Ping , Wang Yong-Xiang 

TITLE=Cynandione A Alleviates Neuropathic Pain Through α7-nAChR-Dependent IL-10/β-Endorphin Signaling Complexes

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 11 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.614450

DOI=10.3389/fphar.2020.614450

ISSN=1663-9812

ABSTRACT=Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia in neuropathic pain. Intrathecal injection of cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased spinal expression of IL-10 and β-endorphin but not dynorphin A. Cynandione A treatment also increased IL-10 and β-endorphin expression in cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical allodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical allodynia but not spinal or microglial IL-10 gene expression. The α7 nicotinic acetylcholine receptor (nAChR) antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. These findings suggest that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAchR activation.