N-Demethylsinomenine Relieves Neuropathic Pain in Male Mice Mainly via Regulating α2-Subtype GABA Receptors.

Aims: N-Demethylsinomenine (NDSM) demonstrates good analgesic efficacy in preclinical pain models. However, how NDSM exerts analgesic actions remains unknown.

Methods: We examined the analgesic effects of NDSM using both pain-evoked and pain-suppressed behavioral assays in two persistent pain models. Then western blot assay and immunofluorescence staining were used to investigate the effects of NDSM on the expression of the GABA receptor α2 subunit (GABRA2) and inflammatory factors in the spinal cord and brain tissues of male spared nerve injury (SNI) mice. Finally, the individual subtypes of GABARs (α1, α2, α3, and α5) were respectively silenced by viral-mediated knockdown to explore the involvement of subtypes of GABARs in the effects of NDSM on the pain-like behaviors in male SNI mice.

Results: NDSM demonstrated significant analgesic effects against chronic pain both in pain-evoked and pain-suppressed behavioral assays. NDSM treatment significantly reversed the SNI induced down-regulation of GABRA2 and up-regulation of TNF-α and IL-1β. The analgesic effects of NDSM were completely blocked by silencing GABRA2 or partially blocked by silencing GABRA3.

Conclusion: This study provided the first evidence that the analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3, and the inhibition of neuroinflammation also contributes to the analgesic effects of NDSM.