Influence of the descending pain-inhibiting serotonergic pathway on the antihyperalgesic effect of gabapentin in neuropathic pain model rats

Gabapentinoids are used worldwide as first-line agents for the treatment of neuropathic pain. Accumulating evidence indicates that one of the antihyperalgesic mechanisms of gabapentinoids is through activation of the noradrenergic pathway of the descending pain inhibition system. However, the involvement of the serotonin pathway is unclear. We investigated the effects of gabapentin (GBP) on the serotonergic pathway of the descending inhibitory system using the spinal nerve ligation (SNL) rat model. As in previous reports, administration of GBP to SNL rats improved paw withdrawal thresholds (PWT). Intrathecally administered serotonin receptor antagonists abolished GBP's amelioration in PWT. GBP did not ameliorate PWT in noradrenaline-depleted SNL rats by DSP-4. However, GBP ameliorated PWT in serotonin-depleted SNL rats by para-chlorophenylalanine, which was not inhibited by intrathecal administration of a serotonin receptor antagonist. Immunohistochemical analysis of serotonin in the spinal dorsal horn revealed a slight, albeit statistically insignificant, increase in 5-HT levels in SNL rats compared to naive rats. However, no apparent changes were observed before or after GBP administration in naive and SNL rats. In conclusion, the involvement of the serotonergic pathway in the antihyperalgesic effects of GBP on the spinal cord is secondary, although it cooperates with the noradrenergic system to produce analgesia.