Spinal 5-HT_1A Receptor-Related and Microglial Mechanisms Associated With Intrathecal Cannabidiol-Induced...

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.