Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo Ward, Niigata City 951-8510, Japan.
Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo Ward, Niigata City 951-8510, Japan; Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Japan.
Neurosci Res. 2024 May;202:20-29. doi: 10.1016/j.neures.2023.11.003. Epub 2023 Nov 8.
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.
加巴喷丁类药物在世界范围内被用作治疗神经性疼痛的一线药物。越来越多的证据表明，加巴喷丁类药物的一种抗痛觉过敏机制是通过激活下行疼痛抑制系统的去甲肾上腺素能途径。然而，其涉及的 5-羟色胺途径尚不清楚。我们使用脊神经结扎（SNL）大鼠模型研究了加巴喷丁（GBP）对下行抑制系统 5-羟色胺能途径的影响。与之前的报告一样，给予 SNL 大鼠 GBP 可改善足底撤回阈值（PWT）。鞘内给予 5-羟色胺受体拮抗剂可消除 GBP 对 PWT 的改善作用。DSP-4 耗尽去甲肾上腺素后，GBP 不能改善 SNL 大鼠的 PWT。然而，对氯苯丙氨酸耗尽 5-羟色胺的 SNL 大鼠中，GBP 可改善 PWT，而鞘内给予 5-羟色胺受体拮抗剂不能抑制这种作用。脊髓背角 5-羟色胺的免疫组织化学分析显示，与正常大鼠相比，SNL 大鼠脊髓背角 5-HT 水平略有升高，但无统计学意义。然而，在正常和 SNL 大鼠中，GBP 给药前后均未观察到明显变化。总之，尽管 5-羟色胺能途径与去甲肾上腺素能系统合作产生镇痛作用，但它在 GBP 对脊髓的抗痛觉过敏作用中的参与是次要的。
