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

Abstract

Cyclovirobuxine D (CVB-D), the main active constituent of traditional Chinese medicine <i>Buxus microphylla</i>, was developed as a safe and effective cardiovascular drug in China. <i>B. microphylla</i> 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_v2.2 and Ca_v3.2 channels but has negligible effects on a diverse group of nociceptive ion channels distributed in primary afferent neurons, including Na_v1.7, Na_v1.8, TRPV1, TPRA1, TRPM8, ASIC3, P₂X₂ and P₂X₄. Moreover, inhibition of Ca_v3.2, rather than Ca_v2.2, 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 <i>via</i> blockade of Ca_v3.2 and provides a compelling rationale and foundation for conducting clinical studies to repurpose cyclovirobuxine D in pain management.