The aconitine analog bulleyaconitine A exhibits anti-hypersensitivity through direct stimulation of dynorphin A release from spinal microglia in the rat model of neuropathy

摘要

Aim Aconitine and its structurally-related diterpenoid alkaloids have been shown to interact differential- ly with neuronal voltage-dependent sodium channels and be responsible for their analgesia and toxicity. Bulleya- conitine A （ BAA or BLA） is an aconitine analog and has been prescribed for the management of pain. The present study aimed to evaluate the inhibitory effects of BAA on pain hypersensitivity and morphine anti-nociceptive toler- ance, and explore whether the release of dynorphin A from spinal microglia was associated with its mechanism of actions. Methods Rat models of neuropathic pain, formalin test and bone cancer pain were used, and spinal dynorphin A level and expression were measured. Sample size of animals was six in each study group. Resultes A single intrathecal or subcutaneous （but not intraventricular or local） injection of BAA blocked spinal nerve liga- tion-induced painful neuropathy, bone cancer-induced pain and formalin-induced hyperalgesia by 60% - 100% with the ED50 values of 94 - 126 ng/rat （intrathecal） and 42 - 59 μg · kg^-1 （ subcutaneous）, respectively. Follow- ing chronic treatment, BAA did not induce either self-tolerance to anti-nociception or cross-tolerance to morphine anti-nociception, and completely prevented morphine tolerance. Spinal BAA anti-nociception, but not neurotoxici- ty, was completely blocked by the specific microglial inhibitor minocycline. In a minocycline-sensitive and lido- BAA stimulated the release of dynorphin A from the spinal cord, and the caine- or ropivacaine-insensitive manner, primary culture of microglia but not from neurons or astrocytes. The blockade effects of BAA on nociception and morphine tolerance were completely blocked by the specific dynorphin A antiserum and/or K-opioid receptor antago- nist. Conclusions Our results demonstrated that BAA eliminated pain hypersensitivity and morphine tolerance through the direct stimulation of dynorphin A release from spinal microglia, which was not dependent on the interac- tions with sodium channels.