Aconitines, including
bulleyaconitine A, probably the most bioactive and abundant
alkaloids in Aconitum plant, are a group of diester C19-diterpenoid
alkaloids with one acetylester group attached to C8 of the
diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that
bulleyaconitine A produced anti-
hypersensitivity, which was mediated by stimulation of spinal microglial
dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in
aconitine-induced
dynorphin A expression, anti-
hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of
aconitine and
benzoylaconine (but not
aconine) attenuated
mechanical allodynia and heat
hyperalgesia, with normalized ED50 values of 35 pmol and 3.6 nmol, respectively.
Aconitine and
benzoylaconine anti-
allodynia was completely blocked by the microglial inhibitor,
dynorphin A antiserum, and κ-
opioid receptor antagonist.
Aconitine and
benzoylaconine, but not
aconine, stimulated
dynorphin A expression in cultured primary spinal microglia, with EC50 values of 32 nM and 3 μM, respectively. Intrathecal
aconitine,
benzoylaconine and
aconine induced flaccid
paralysis and death, with normalized TD50 values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD50/ED50 ratios of
aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for
aconitine to stimulate spinal microglial
dynorphin A expression and subsequent anti-
hypersensitivity, which can be separated from neurotoxicity, because both
benzoylaconine and
aconine differentially produced anti-
hypersensitivity and neurotoxicity due to their different stimulatory ability on
dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to avoid overprocessing and excess hydrolysis of benzolyaconine to
aconine.