Department of Neuroscience Physiology and Pharmacology, University College London, Gower Street, London WC1E6BT, UK.
Neurosci Lett. 2010 Oct 29;484(2):108-12. doi: 10.1016/j.neulet.2010.08.024. Epub 2010 Aug 13.
We have recently reported the importance of spinal rapamycin-sensitive pathways in maintaining persistent pain-like states. A descending facilitatory drive mediated through spinal 5-HT3 receptors (5-HT3Rs) originating from superficial dorsal horn NK1-expressing neurons and that relays through the parabrachial nucleus and the rostroventral medial medulla to act on deep dorsal horn neurons is known be important in maintaining these pain-like states. To determine if spinal rapamycin-sensitive pathways are activated by a descending serotonergic drive, we investigated the effects of spinally administered rapamycin on responses of deep dorsal horn neurons that had been pre-treated with the selective 5-HT3R antagonist ondansetron. We also investigated the effects of spinally administered cell cycle inhibitor (CCI)-779 (a rapamycin ester analogue) on deep dorsal horn neurons from rats with carrageenan-induced inflammation of the hind paw. Unlike some other models of persistent pain, this model does not involve an altered 5-HT3R-mediated descending serotonergic drive. We found that the inhibitory effects of rapamycin were significantly reduced for neuronal responses to mechanical and thermal stimuli when the spinal cord was pre-treated with ondansetron. Furthermore, CCI-779 was found to be ineffective in attenuating spinal neuronal responses to peripheral stimuli in carrageenan-treated rats. Therefore, we conclude that 5-HT3R-mediated descending facilitation is one requirement for activation of rapamycin-sensitive pathways that contribute to persistent pain-like states.
我们最近报道了脊髓雷帕霉素敏感途径在维持持续性疼痛样状态中的重要性。一种起源于浅层背角 NK1 表达神经元的、通过脊髓 5-HT3 受体（5-HT3R）介导的下行易化驱动，通过臂旁核和头腹侧 medulla 的中继，作用于深部背角神经元，在维持这些疼痛样状态中起着重要作用。为了确定脊髓雷帕霉素敏感途径是否被下行 5-羟色胺能驱动激活，我们研究了鞘内给予雷帕霉素对预先用选择性 5-HT3R 拮抗剂昂丹司琼预处理的深部背角神经元反应的影响。我们还研究了鞘内给予细胞周期抑制剂（CCI）-779（雷帕霉素酯类似物）对卡拉胶诱导的后爪炎症大鼠深部背角神经元的影响。与其他一些持续性疼痛模型不同，这种模型不涉及改变的 5-HT3R 介导的下行 5-羟色胺能驱动。我们发现，当脊髓预先用昂丹司琼处理时，雷帕霉素对机械和热刺激引起的神经元反应的抑制作用显著降低。此外，CCI-779 被发现不能减轻卡拉胶处理大鼠脊髓神经元对周围刺激的反应。因此，我们得出结论，5-HT3R 介导的下行易化是激活雷帕霉素敏感途径的一个要求，这些途径有助于持续性疼痛样状态。
