Studies on Mechanism of Intractable Pain wih Animal Models

PG诱导的异常性疼痛的机制我们之前表明，鞘内（i.t）施用PGE 2 和PGF2α可在清醒的小鼠中诱导触摸诱发的疼痛（异常性疼痛）。通过新生儿辣椒素治疗选择性消除 C 纤维会导致 PGE 2 引起的异常性疼痛消失，但 PGF2α 引起的异常性疼痛不会消失。在 NMDA 受体 ε1 亚基敲除小鼠和对吗啡敏感的小鼠中未观察到 PGE2 诱导的异常性疼痛。相比之下，在 NMDA ε4 亚基敲除小鼠中未观察到 PGF2α 诱导的对吗啡不敏感的小鼠。 PGE 2 引起的异常性疼痛被 NMDA、受体 ε2 拮抗剂 CP-101, 606 消除。PGF2 α 诱导的异常性疼痛不受 CP-101, 606 的影响。这些结果表明，由谷氨酸能系统介导的异常性疼痛有两种诱导途径。给予伤害感受肽引起的热痛觉过敏和触觉异常性疼痛。在本研究中，我们证明辣椒素敏感的初级传入纤维不仅参与热痛觉过敏，而且还参与伤害感受素引起的触觉异常性疼痛，但参与途径不同。前者由 P 物质介导，后者由谷氨酸通过包含 GluR ε1 亚基的 NMDA 受体介导。另一方面，nocistatin 源自与痛敏肽相同的前体，并且它具有阻断痛敏肽和 PG 诱发的疼痛反应的生物活性。此外，诺西他汀阻断福尔马林试验的早期和晚期阶段。

Mechanism of PG-induced allodyniaWe previously showed that intrathecal (i.t.) administration of PGE 2 and PGF2αinduce touch-evoked pain (allodynia) in conscious mice. Selective elimination of C-fibers by neonatal capsaicin treatment results in the disappearance of allodynia induced by PGE 2, but not byPGF2α. PGE2- induced allodynia was not observed in NMDA receptor ε1 subunit knockout mice and sensitive to morphine. In contrast, PGF2α-induced one was not observed in NMDA ε4 subunit knockout mice and insensitive to morphine. The induction of allodynia by PGE 2 was abolished by the NMDA, receptor ε2 antagonist CP-101, 606. PGF2 α-induced allodynia was not affected by CP- 101, 606. These results demonstrate that there are two pathways for induction of allodynia mediated by the glutamatergic system.Roles of nociceptin and nocistatin in pain transmissionWe recently showed that i.t. administration of nociceptin induced thermal hyperalgesia and tactile allodynia. In the present study, we demonstrate that capsaicin-sensitive primary afferent fibers are involved not only in thermal hyperalgesia but also in tactile allodynia induced by nociceptin, but in different pathways ; the former is mediated by substance P and the latter is mediated by glutamate through the NMDA receptor comprising GluR ε1 subunit. On the other hand, nocistatin is derived from the same precursor as nociceptin, and it has biological activity which blocks the nociceptin- and PGs-evoked pain responses. Furthermore nocistatin blocks both the early and the late phases in the formalin test.