The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting Na_V1.7 and Na_V1.8 nociceptive sodium channels

Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons. We show that THC directly targets the nociceptive voltage-gated sodium channels Na_V1.7 and Na_V1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons. Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of Na_V1.7 and Na_V1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.