Piezo2 mediates cannabidiol-induced analgesia of mechanical allodynia
Abstract
Cannabidiol (CBD), a clinically approved but non-psychoactive component of cannabis, has demonstrated analgesic effects in both human and rodent models of chronic pain1-6. However, the molecular mechanisms underlying CBD’s analgesic properties, particularly in mechanical allodynia, remain unclear. The mechanically activated ion channel Piezo2 is a genetically validated mechanoreceptor for touch and mechanical allodynia in both humans and mice7-11. Here, we show that both systemic (intraperitoneal) and local (intraplantar) administration of CBD into wild-type mice specifically suppress behavioral responses to gentle touch and mechanical allodynia in pain models, without affecting responses to noxious heat or heat hyperalgesia. Importantly, the specific effects on touch and mechanical allodynia are abolished in Piezo2-deficient mice. Mechanistically, CBD inhibits Piezo2-mediated mechanically activated and rapidly adapting currents in primary sensory neurons and in heterologous cells expressing mouse Piezo2. CBD directly binds to purified Piezo2 proteins with measurable affinity. Additionally, CBD inhibits human PIEZO2-mediated mechanically evoked currents. These findings identify Piezo2 as a long-sought-after receptor mediating CBD’s analgesic effects in mechanical allodynia, validate Piezo2 as a promising non-opioid analgesic target, and provide a mechanistic foundation for developing CBD-derived pain therapies.
References
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