AUTHOR=Su Deyuan , Gong Ye , Li Songyu , Yang Jian , Nian Yin 

TITLE=Cyclovirobuxine D, a cardiovascular drug from traditional Chinese medicine, alleviates inflammatory and neuropathic pain mainly via inhibition of voltage-gated Cav3.2 channels

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1081697

DOI=10.3389/fphar.2022.1081697

ISSN=1663-9812

ABSTRACT=<p>Cyclovirobuxine D (CVB-D), the main active constituent of traditional Chinese medicine <italic>Buxus microphylla</italic>, was developed as a safe and effective cardiovascular drug in China. <italic>B. microphylla</italic> has also been used to relieve various pain symptoms for centuries. In this study, we examined and uncovered strong and persistent analgesic effects of cyclovirobuxine D against several mouse models of pain, including carrageenan- and CFA-induced inflammatory pain and paclitaxel-mediated neuropathic hypersensitivity. Cyclovirobuxine D shows comparable analgesic effects by intraplantar or intraperitoneal administration. Cyclovirobuxine D potently inhibits voltage-gated Ca<sub>v</sub>2.2 and Ca<sub>v</sub>3.2 channels but has negligible effects on a diverse group of nociceptive ion channels distributed in primary afferent neurons, including Na<sub>v</sub>1.7, Na<sub>v</sub>1.8, TRPV1, TPRA1, TRPM8, ASIC3, P<sub>2</sub>X<sub>2</sub> and P<sub>2</sub>X<sub>4</sub>. Moreover, inhibition of Ca<sub>v</sub>3.2, rather than Ca<sub>v</sub>2.2, plays a dominant role in attenuating the excitability of isolated dorsal root ganglion neurons and pain relieving effects of cyclovirobuxine D. Our work reveals that a currently in-use cardiovascular drug has strong analgesic effects mainly <italic>via</italic> blockade of Ca<sub>v</sub>3.2 and provides a compelling rationale and foundation for conducting clinical studies to repurpose cyclovirobuxine D in pain management.</p>