Intrathecal Cannabidiol Reverses Neuropathic Pain in Mice via Spinal 5-HT1A Receptors and Microglial Modulation

Current pharmacological treatments for neuropathic pain often prove ineffective, leaving many patients with persistent, debilitating symptoms. The complex mechanisms underlying neuropathic pain, including central sensitization and neuroinflammation, necessitate novel therapeutic strategies. Cannabidiol (CBD) has shown promise as an analgesic, but its clinical utility is hampered by poor oral bioavailability and a short half-life. This study explores the potential of direct spinal delivery of cannabidiol to overcome these limitations and investigates its specific mechanisms, particularly focusing on spinal 5-HT1A receptors and microglial activity, which are key modulators of pain signaling and neuroinflammation.

Male C57BL/6 mice were subjected to chronic constriction injury (CCI) to induce neuropathic pain. Mechanical nociceptive thresholds were assessed using von Frey filaments as the primary endpoint. The study compared the effects of intrathecal (i.t.) cannabidiol administration against oral administration. To investigate the role of spinal 5-HT1A receptors, the selective antagonist WAY-100635 was co-administered intrathecally. Researchers also evaluated mRNA expression of 5-HT1A receptors, spinal IL-10 and TNF-α levels, and microglial activation using immunohistochemistry and qPCR in spinal cord tissue. In vitro experiments further assessed cannabidiol's effects on microglial activation and TNF-α production.

Intrathecal cannabidiol significantly reversed mechanical allodynia in CCI mice, demonstrating a more potent and prolonged antinociceptive effect compared to oral administration. This analgesic effect was completely abolished by the co-administration of WAY-100635, strongly indicating the involvement of spinal 5-HT1A receptors in cannabidiol's action. Furthermore, i.t. cannabidiol led to a notable increase in spinal IL-10 levels and 5-HT1A receptor mRNA expression. Concurrently, it significantly reduced microglial activation in the spinal cord, suggesting an anti-inflammatory and neuroimmunomodulatory role.

In vitro, cannabidiol directly attenuated microglial activation and significantly reduced the production of the pro-inflammatory cytokine TNF-α, reinforcing its direct impact on neuroinflammation.