Ca permeable non-NMDAr: New spinal sensitization pathway

描述(由申请人提供)： NMDA受体(NMDAR)的激活允许钙离子跨膜流动，从而 诱导脊髓敏感化，激活信号转导级联和 痛觉过敏。然而，钙离子通透性非NMDA受体的激活 (CA-渗透性非NMDAR)，在没有NMDAR任何帮助的情况下，也可以生产 突触强化和信号转导的激活级联作用。近期 使用NMDAR拮抗剂不敏感的疼痛模型的研究表明，鞘内 给予钙离子渗透性非NMDA受体拮抗剂，阻断或 逆转继发性机械过敏症。相同的药剂在 一些NMDA敏感(依赖)的继发性痛觉过敏模型。这导致了 假设：钙离子通透性AMPA受体激活可诱导脊髓 不同于NMDA的启动机制引起的敏化和痛觉过敏 受体激活。第三组疼痛模型部分依赖NMDAR 激活。足底内热性和机械性痛觉过敏 角叉菜胶能被NMDA或钙渗透型非NMDAR同样很好地阻断 对抗者。在辣椒素或C纤维刺激后，ERK(成员 丝裂原活化蛋白激酶信号级联反应)和转录因子 CREB(cAMP反应结合蛋白)被磷酸化。然而，较少 NMDAR拮抗剂可阻断一半以上的磷酸化。 其余的是由作用于NMDAR以外的受体的药物引起的， 也许包括钙渗透性的非NMDAR。如果钙渗透型非NMDAR是 负责任的是，这意味着NMDAR和钙渗透之间的融合 ERK激活前的非NMDAR诱导通路。作为烧伤和烧伤的模型 手术后疼痛，其中钙渗透性非NMDAR可能起作用 一个作用，类似于临床情况，这一新的变离子途径可能 在至少一些临床疼痛状态的产生中起着重要作用。 我们建议研究钙通透性的非NMDAR激活对 ERK和CREB的磷酸化(用Western blotts和免疫组织化学)， C-fos的表达与痛觉过敏的发生。

DESCRIPTION (provided by applicant): NMDA receptor (NMDAr) activation allows Ca2+ flux across the membrane that induces spinal sensitization, activation of signal transduction cascades and hyperalgesia. However, activation of Ca2+ permeable non-NMDA receptors (Ca-permeable non-NMDAr), without any help from NMDAr, can also produce synaptic strengthening and activation of signal transduction cascades. Recent work using NMDAr antagonist-insensitive models of pain shows that intrathecal administration of a Ca2+ permeable non-NMDA receptor antagonist, blocks or reverses secondary mechanical allodynia. The same agent is without effect in some NMDA-sensitive (dependent) models of secondary hyperalgesia. This leads to the hypothesis: Ca2+ permeable AMPA receptor activation can induce spinal sensitization and hyperalgesia via an initiating mechanism distinct from NMDA receptor activation. A 3rd group of pain models is partially dependent on NMDAr activation. Thermal and mechanical hyperalgesia following intraplantar carrageenan are blocked equally well by either NMDA or Ca-permeable non-NMDAr antagonists. After capsaicin or C-fiber stimulation, ERK (member of the mitogen-activated protein kinase signaling cascade) and transcriptional factor CREB (cAMP responsive binding protein) become phosphorylated. However, less than half of the phosphorylation is blocked by NMDAr antagonist pretreatment. The remainder is elicited by agents acting on receptors other than NMDAr, perhaps including Ca-permeable non-NMDAr. If Ca-permeable non-NMDAr are responsible, this implies a convergence between NMDAr- and Ca-permeable non-NMDAr-induced pathways prior to ERK activation. As models of burn and post-surgical pain, in which Ca-permeable non-NMDAr presumably appears to play a role, resemble clinical conditions, this novel ionotropic pathway probably plays a significant part in generation of at least some clinical pain states. We propose to investigate the effects of Ca-permeable non-NMDAr activation on ERK and CREB phosphorylation (using Western blots and immunohistochemistry), expression of c-fos and development of hyperalgesia.