The natural product Argentatin C attenuates postoperative pain via inhibition of voltage-gated sodium and T-type voltage-gated calcium channels

Paz Duran, Santiago Loya-López, Dongzhi Ran, Cheng Tang, Aida Calderon-Rivera, Kimberly Gomez, Harrison J. Stratton, Sun Huang, Ya ming Xu, E. M.Kithsiri Wijeratne, Samantha Perez-Miller, Zhiming Shan, Song Cai, Anna T. Gabrielsen, Angie Dorame, Kyleigh A. Masterson, Omar Alsbiei, Cynthia L. Madura, Guoqin Luo, Aubin MoutalJohn Streicher, Gerald W. Zamponi, A. A.Leslie Gunatilaka, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review

Abstract

Background and purpose: Postoperative pain occurs in as many as 70% of the over 230 million surgeries performed annually worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is of utmost importance to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel and biologically active compounds for development of safe analgesics. Hence, in this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels which have important roles in nociceptive sensory processing. Experimental approach: Fractions derived from the Native American medicinal plant, Parthenium incanum, were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Further separation of these fractions yielded a cycloartane-type triterpene identified as argentatin C, which was additionally evaluated using whole-cell voltage and current clamp electrophysiology, and behavioral analysis in a mouse model of postsurgical pain. Key Results: We found that argentatin C blocked the activity of both voltage-gated sodium and LVA calcium channels in calcium imaging assays. Docking analysis predicted that argentatin C may bind to NaV1.7-1.9 and CaV3.1-3.3 channels. Furthermore, argentatin C decreased Na+ and T-type Ca2+ currents as well as excitability in rat and macaque DRG neurons. Consistent with these observations, argentatin C treatment reversed mechanical allodynia in a mouse model of postsurgical pain. Conclusions & Implications: These results suggest that the dual effect of argentatin C on voltage-gated sodium and calcium channels supports its potential as a novel treatment for painful conditions.

Original languageEnglish (US)
JournalBritish Journal of Pharmacology
DOIs
StateAccepted/In press - 2022

Keywords

  • Natural compounds
  • T-type
  • argentatin
  • neuropathic pain
  • voltage-gated calcium channels
  • voltage-gated sodium channels

ASJC Scopus subject areas

  • Pharmacology

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