title: Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats.
abstract: Paclitaxel, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and at present no effective drug is available for treatment of the serious side effect. Here, we tested if intragastrical application of bulleyaconitine A (BLA), which has been approved for clinical treatment of chronic pain in China since 1985, could relieve the paclitaxel-induced neuropathic pain. A single dose of BLA attenuated the mechanical allodynia, thermal hyperalgesia induced by paclitaxel dose-dependently. Repetitive administration of the drug (0.4 and 0.8 mg/kg, t.i.d. for 7 d) during or after paclitaxel treatment produced a long-lasting inhibitory effect on thermal hyperalgesia, but not on mechanical allodynia. In consistency with the behavioral results, in vivo electrophysiological experiments revealed that spinal synaptic transmission mediated by C-fiber but not A fiber was potentiated, and the magnitude of long-term potentiation (LTP) at C-fiber synapses induced by the same high frequency stimulation was ~50% higher in paclitaxel-treated rats, compared to the naïve rats. Spinal or intravenous application of BLA depressed the spinal LTP, dose-dependently. Furthermore, patch clamp recordings in spinal cord slices revealed that the frequency but not amplitude of both spontaneous excitatory postsynaptic current (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in lamina II neurons was increased in paclitaxel-treated rats, and the superfusion of BLA reduced the frequency of sEPSCs and mEPSCs in paclitaxel-treated rats but not in naïve ones. Taken together, we provide novel evidence that BLA attenuates paclitaxel-induced neuropathic pain and that depression of spinal LTP at C-fiber synapses via inhibiting presynaptic transmitter release may contribute to the effect.
authors.affiliation: Department of Physiology and Pain Research Center,Zhongshan School of Medicine SunYat-sen University,Guangzhou510080,China.
authors.forename: He-Quan
authors.initials: HQ
authors.lastname: Zhu
authors.affiliation: Department of Physiology and Pain Research Center,Zhongshan School of Medicine SunYat-sen University,Guangzhou510080,China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery,Xinqiao Hospital,Third Military Medical University,Chongqing400037,China.
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Shen
authors.affiliation: Department of Physiology and Pain Research Center,Zhongshan School of Medicine SunYat-sen University,Guangzhou510080,China.
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Pang
authors.affiliation: Department of Physiology and Pain Research Center,Zhongshan School of Medicine SunYat-sen University,Guangzhou510080,China. Electronic address: weixhong@mail.sysu.edu.cn.
authors.forename: Xu-Hong
authors.initials: XH
authors.lastname: Wei
authors.affiliation: Department of Physiology and Pain Research Center,Zhongshan School of Medicine SunYat-sen University,Guangzhou510080,China. Electronic address: liuxg@mail.sysu.edu.cn.
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D066298:In Vitro Techniques; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000502:physiology; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects*; D055366:Synaptic Potentials / Q000187:drug effects; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C052509:bulleyaconitine A; D017239:Paclitaxel; D000157:Aconitine
keywords: Bulleyaconitine A; C-fiber; Long-term potentiation; Neuropathic pain; Paclitaxel