Ca permeable non-NMDAr: New spinal sensitization pathway

描述（由申请人提供）： NMDA受体（NMDAr）激活允许Ca 2+穿过膜， 诱导脊髓致敏，激活信号转导级联， 痛觉过敏然而，Ca 2+渗透性非NMDA受体的激活 （钙渗透性非NMDAr），没有NMDAr的任何帮助，也可以产生 突触强化和信号转导级联的激活。最近 使用NMDA受体拮抗剂不敏感的疼痛模型的工作表明，鞘内注射 施用Ca 2+可渗透的非NMDA受体拮抗剂，阻断或 逆转继发性机械异常性疼痛。同样的药剂在 继发性痛觉过敏的一些NMDA敏感（依赖）模型。这导致 Ca 2+渗透性AMPA受体激活可诱导脊髓 通过不同于NMDA的起始机制的敏化和痛觉过敏 受体激活第三组疼痛模型部分依赖于NMDAr activation.足底热痛敏和机械痛敏 角叉菜胶被NMDA或Ca-可渗透的非NMDA受体同样良好地阻断 对手。在辣椒素或C-纤维刺激后，ERK（细胞外基质中的一员） 有丝分裂原活化蛋白激酶信号级联）和转录因子 CREB（cAMP反应性结合蛋白）被磷酸化。然而， 超过一半的磷酸化被NMDAr拮抗剂预处理阻断。 其余的由作用于NMDAr以外的受体的药剂引起， 可能包括Ca可渗透的非NMDAr。如果钙渗透性非NMDAr 负责任，这意味着NMDAr-和Ca-渗透之间的收敛 ERK激活前的非NMDAr诱导途径。作为烧伤和 手术后疼痛，其中钙渗透性非NMDAr可能似乎起作用 作用，类似于临床条件，这种新的离子型途径可能 在至少一些临床疼痛状态的产生中起重要作用。 我们建议研究钙渗透性非NMDAr激活对 ERK和CREB磷酸化（使用蛋白质印迹和免疫组织化学）， 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.