Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat.
Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat.
复制标题
DOI：
10.1186/1744-8069-7-86
复制
发表时间：
2011-11-05
期刊：
影响因子：
3.3
通讯作者：
McMahon SB
中科院分区：
文献类型：
--
作者：
Marchand F;D'Mello R;Yip PK;Calvo M;Muller E;Pezet S;Dickenson AH;McMahon SB
中枢敏感化需要激活脊髓背角神经元内的各种细胞内信号通路，导致这些细胞的激活阈值降低和反应性增强。这种可塑性有助于慢性疼痛状态的表现，并显示出许多长时程增强(LTP)的特征，LTP是一种普遍存在的突触强度增加的神经机制。在这里，我们描述了一种新的途径，涉及非典型的PKCζ/PKMζ在持续性脊髓伤害性信息处理中的作用，以前曾被认为与晚期LTP的维持有关。在大鼠的行为学测试和体内电生理学研究中，我们发现，通过脊髓注射肉豆蔻酰化蛋白激酶C-ζ假底物抑制剂，抑制这一通路，可以减少福尔马林注射后的痛相关行为和深背角宽动态范围神经元(WDRs)的活动。此外，完全弗氏佐剂还可通过抑制PKCζ/PKMζ活性而降低机械和温度超敏反应。重要的是，这种抑制并没有影响正常大鼠的急性疼痛或运动行为，有趣的是，也没有抑制神经病大鼠的机械性痛觉异常和痛觉过敏。两种炎症模型的疼痛相关行为均与背角神经元PKCζ/PKMζ的磷酸化增强相一致，尤其是福尔马林大鼠的PKMζ的磷酸化。最后，抑制PKCζ/PKMζ活性降低了福尔马林和CFA对背角浅层和深层Fos表达的影响。这些结果表明，PKCζ，特别是PKMζ亚型，是参与脊髓持续性伤害性反应的重要因素，尤其是在外周炎症后慢性疼痛状态的表现。
Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP), a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs) following formalin administration. In addition, Complete Freund's Adjuvant (CFA)-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.
登录
查看更多内容
影响因子：
5.3
作者：
Martin, WJ;Malmberg, AB;Basbaum, AI
通讯作者：
Basbaum, AI
影响因子：
3.3
作者：
Asante, Curtis O.;Wallace, Victoria C.;Dickenson, Anthony H.
通讯作者：
Dickenson, Anthony H.
影响因子：
56.9
作者：
Ikeda, Hiroshi;Stark, Johanna;Sandkuhler, Jurgen
通讯作者：
Sandkuhler, Jurgen
影响因子：
7.4
作者：
Lang, Stefanie;Klein, Thomas;Treede, Rolf-Detlef
通讯作者：
Treede, Rolf-Detlef
影响因子：
4.8
作者：
Hernandez, AI;Blace, N;Sacktor, TC
通讯作者：
Sacktor, TC