Spinal 5‐HT 1A Receptor‐Related and Microglial Mechanisms Associated With Intrathecal Cannabidiol‐Induced Antinociception in Neuropathic Pain

Although first‐line pharmacological treatments for neuropathic pain are often ineffective, cannabidiol has shown promise. However, the analgesic effects of orally administered, cannabidiol are limited by low bioavailability and a short half‐life. Therefore, this study investigated the effects of intrathecal (i.t.), cannabidiol administration on neuropathic pain, focusing on spinal 5‐HT 1A receptors and microglial modulation. Male C57BL/6 mice were subjected to neuropathic pain‐induced by chronic constriction injury (CCI). Mechanical nociceptive thresholds were assessed using von Frey filaments. The involvement of spinal 5‐HT 1A receptors was examined by i.t. administration of the selective antagonist WAY‐100635. mRNA expression, IL‐10, and TNF‐α levels, and microglial activation were evaluated. Intrathecal, cannabidiol significantly reversed mechanical allodynia, producing a more potent and prolonged antinociceptive effect than oral administration. This effect was abolished by WAY‐100635, indicating spinal 5‐HT 1A receptor involvement. Moreover, i.t. cannabidiol increased spinal IL‐10 levels and 5‐HT 1A receptor mRNA expression, while reducing microglial activation. In vitro, cannabidiol attenuated microglial activation and significantly reduced TNF‐α production. In conclusion, i.t. cannabidiol effectively alleviates neuropathic pain in mice, with findings that may suggest the involvement of spinal mechanisms associated with 5‐HT 1A receptor‐related signaling and modulation of microglial activation.