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: He-Quan Zhu, Jing Xu, Kai-Feng Shen, Rui-Ping Pang, Xu-Hong Wei, Xian-Guo Liu
• Journal: Experimental neurology (Exp Neurol) Vol. 273 Pg. 263-72 (Nov 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 26376216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• bulleyaconitine A
• Paclitaxel
• Aconitine

Topics

• Aconitine (analogs & derivatives, pharmacology, therapeutic use)
• Analysis of Variance
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electric Stimulation
• Evoked Potentials (drug effects)
• Hyperalgesia (drug therapy, etiology)
• In Vitro Techniques
• Male
• Nerve Fibers, Unmyelinated (drug effects, physiology)
• Neuralgia (chemically induced, drug therapy, pathology)
• Paclitaxel (pharmacology)
• Pain Measurement
• Pain Threshold (drug effects)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord Dorsal Horn (drug effects)
• Synaptic Potentials (drug effects)
• Time Factors