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

- Cynandione A is the principle acetophenone of Cynanchi Wilfordii Radix.
- Intrathecal injection of cynandione A produced antinociception in neuropathic rats.
- Cynandione A stimulated β-endorphin expression in spinal microglia.
- p38β MAPK mediated cynandione A-induced β-endorphin release and antiallodynia.

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 14.9 μg and 6.5 μg, 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 20.0 μM, 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.

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