Mechanism Underlying Lappaconitine Antinociception In Chronic Pain

Aconitum Sinomontanum Nakai,is one of crowfoot plants of the genus Aconitum,mainly distributed in Sichuan?Guizhou?Qinghai and other places of China.The medicinal part of it is its dry root and it can relieve pain?activate blood circulation and has wind-dampness-eliminating effect.It can be used in the treatment of fracture?lumbocrural pain and stomach pain.Lappaconitine is the highest ingredient among these terpenoids alkaloids and used for the treatment of light or medium degree of pain clinically.Our many researches have showed that the anti-nociception effects of these aconitum alkaloids could be separated from their toxicity and the mechanism of their analgesia was related to stimulating the release of dynorphin A and the activation of spinal?-opioid receptors while the interference with sodium channels had more relationship with their toxicity on neurons in the central nervous system.This study aimed to investigate the analgesic effects of Lappaconitine on the L₅/L₆ spinal nerve ligated-induced neuropathic pain and bone cancer-induced pain.The results showed that cumulatively subcutaneous or singlely intrathecal injection of Lappaconitine blocked spinal nerve ligation-induced neuropathic pain and bone-cancer induced pain by 50 to 80%with the median effective dose values of 0.8?g?intrathecal?and 1.1 to 2.6 mg/kg?subcutaneous?,respectively and Lappaconitine did not induce self-tolerance to neuropathic pain and it did not reach the purpose of cure the pain.Lappaconitine stimulated the expression of dynorphin A in the spinal cord and primary cultures of microglia but not of neurons or astrocytes via in vitro and vivo experiments.Intrathecal the dynorphin A antibody and?-opioid receptor antagonist GNTI suppressed Lappaconitine-induced anti-nociception.Furthermore,in the model of neuropathic pain,intrathecal injection of noradrenaline and serotonin depletors 6-OHDA and PCPA and selective?-receptor antagonist phentolamine and serotonin antagonist metergolin respectively did not block the antinociceptive effect of Lappaconitine.Our results suggested that Lappaconitine exhibited antihypersensitivity through direct stimulating dynorphin A expression in spinal microglia,which was not dependent on the interactions with spinal norepinephrine and serotonin descending inhibitory system according some research reported and sodium channels which we thought had a great relationship with its toxicity.This study stated the relationship between the structures and the analgesic effects of these aconitum alkaloids and proved that all of them could stimulate dynorphin A expression in spinal microglia to produce analgesic action.