Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol.

Cannabis-derived compounds, particularly the non-psychoactive cannabidiol (CBD), hold significant potential for pain management. However, CBD's hydrophobicity limits systemic brain delivery, constraining both its therapeutic efficacy and mechanistic investigation. Here, we present an inclusion-complex-enhanced nano-micelle formulation (CBD-IN) that significantly improves systemic absorption and elevates brain CBD levels. A single dose of CBD-IN fully suppresses allodynia and hyperalgesia in a mouse model of neuropathic pain, without impairing normal sensorimotor or cognitive functions. This rapid and robust analgesic effect enables in-depth investigation of underlying neural mechanisms. Activity-dependent genetic mapping reveals that CBD-IN selectively reduces allodynia-associated neuronal activation across the somatosensory system. Complementary calcium imaging in spinal nociceptive and somatosensory corticospinal neurons further demonstrates pathophysiological state-dependent neural suppression by CBD. These results demonstrate that nano-formulated CBD delivers rapid and effective analgesia by selectively suppressing pathological hyperactivity throughout the somatosensory system, offering a promising therapeutic strategy for neuropathic pain and other disorders involving circuit-level disinhibition.