Elucidation of mechanism for induction of pain with knockout mice

疼痛的感觉提供了关于损伤发生的有用警告。然而，在病理条件下，例如长期炎症、手术后和神经损伤，外周中的伤害感受器被激活并产生自发性疼痛、痛觉过敏和触觉疼痛（异常性疼痛）。我们以前的研究表明：1）鞘内注射前列腺素（PG）E2和PGF_（2 α）可诱导痛觉超敏; 2）辣椒素敏感和不敏感通路参与痛觉超敏的诱导; 3）PG可能通过启动突触末梢谷氨酸释放→ NMDA受体激活→NO产生的生物化学级联反应而产生痛觉超敏。4)PGD 2可阻断PGE 2诱导的痛觉超敏反应。为了阐明特定成分在基因敲除小鼠诱发异常性疼痛中的作用，我们建立了基因敲除小鼠坐骨神经部分结扎的方法，并获得了以下结果：环氧化酶（COX）是PG产生的限速酶。虽然考克斯-1是组成型，但考克斯-2是诱导型，并被认为是炎症中PG产生的原因。1)尽管在治疗后1周诱导了异常性疼痛，但在考克斯-2^<-/->小鼠中观察到异常性疼痛，表明考克斯-2不参与异常性疼痛的诱导。2)考克斯-1选择性抑制剂，而不是考克斯-2选择性抑制剂，减轻坐骨神经损伤引起的疼痛反应。3)虽然在iNOS^<-/->小鼠中观察到异常性疼痛，但在NMDA^<-/->小鼠中疼痛反应消失。这些结果表明，由PGE 2激活的谷氨酸兴奋性传递在坐骨神经损伤后疼痛的诱导和维持中起着关键作用。为了阐明异常性疼痛的诱导和维持，我们将扩大坐骨神经损伤模型的研究，并将其与i. t. PG异常性疼痛模型。

The sensation of pain provides useful warning about occurrence of injury. However, under pathological conditions such as prolonged inflammation, post-operation, and nerve injury, nociceptors in the periphery become activeted and produce spontaneous pain, hyperalgesia and tactile pain (allodynia). We previously demonstrated that 1) intrathecal administration of prostaglandin (PG) E2 and PGF2α induced allodynia, 2) capsaicin-sensitive and-insensitive pathways were involved in induction of allodynia, 3) PGs may produce allodynia by initiating a biochamical cascade of glutamate release from synaptic terminal→activation of NMDA receptor→NO production. 4) PGD2 blocked the PGE2-induced allodynia. In order to clarify the involvement of a given component in induction of allodynia by use of knockout mice, we established partial sciatic nerve ligation method in the knockout mouse and obtained following results.Cyclooxygenases (COXs) are rate-limiting enzymes for PG production. While COX-1 is a constitutive form, COX-2 is an inducible form and considered to be accounted for PG production in inflammation. 1) Although allodynia was induced 1 week after treatment, allodynia was observed in COX-2^<-/-> mice, suggesting that COX-2 was not involved in the induction of allodynia. 2) The COX-1 selective inhibitor, but not the COX-2 selective inhibitor, alleviated pain responses induced by sciatic nerve injury. 3) While allodynia was observed in iNOS^<-/-> mice, pain responses disappeared in NMDA^<-/-> mice. These results demonstrate that excitatory transmission by glutamate activated by PGE2 plays pivotal roles in induction and maintenance of pain following sciatic nerve injury. In order to elucidate the induction and maintenance of allodynia, we will extend this study of sciatic nerve injury model and compare it with that of i.t. PG allodynia model.