Studies on Mechanism of Intractable Pain wih Animal Models

先前的研究表明，鞘内给药pge2和pgf2 α可诱导有意识小鼠的触觉诱发疼痛（allodynia）。新生儿辣椒素治疗选择性消除c纤维导致pge2诱导的异位性疼痛消失，但不包括byPGF2α。在NMDA受体ε1亚基敲除小鼠中未观察到PGE2诱导的异常性疼痛，且对吗啡敏感。相比之下，pgf2 α-诱导的NMDA ε4亚基敲除小鼠未观察到，且对吗啡不敏感。受体ε2拮抗剂cp - 101,606可消除pge2对异常性疼痛的诱导作用。CP- 101,606对PGF2 α-诱导的异常性痛无影响。这些结果表明，有两种途径的诱导异常性疼痛介导的谷氨酸系统。痛觉肽和去皮抑素在疼痛传递中的作用我们最近发现，注射痛觉肽会引起热痛觉过敏和触觉异常性痛。在本研究中，我们发现辣椒素敏感的初级传入纤维不仅参与痛觉素引起的热痛觉过敏，也参与痛觉素引起的触觉异常性痛，但通路不同；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来源于与痛觉啡肽相同的前体，它具有阻断痛觉啡肽和pgs引起的疼痛反应的生物活性。此外，去皮抑素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.