Parada C A, Yeh J J, Reichling D B, Levine J D
Department of Oral and Maxillofacial Surgery, 521 Parnassus Avenue, Room C-555, Campus Box 0440, NIH Pain Center, University of California, San Francisco, CA 94143-0440, USA.
Neuroscience. 2003;120(1):219-26. doi: 10.1016/s0306-4522(03)00267-7.
Recently we demonstrated that a single 3-day episode of carrageenan-induced acute cutaneous inflammation can create a chronic state of increased susceptibility to inflammatory hyperalgesia. In this latent "primed" state, although there is no ongoing hyperalgesia, the hyperalgesic response to subsequent challenges with inflammatory agent (prostaglandin E2; PGE2) is greatly enhanced. Furthermore, the PGE2-induced hyperalgesia in primed skin was found to require activity of the epsilon isozyme of protein kinase C (PKCepsilon), a second messenger that is not required for PGE2-induced hyperalgesia in control animals. In the present study we tested the hypothesis that activity of PKCepsilon not only plays a critical role in the expression of primed PGE2-induced hyperalgesia, but also in the development and maintenance of the primed state itself. Antisense oligodeoxynucleotide was employed to produce a decrease in PKCepsilon in the nerve, verified by Western blot analysis. PKCepsilon was found to be essential both for the development of carrageenan-induced hyperalgesic priming, as well as for the maintenance of the primed state. Furthermore, hyperalgesic priming could be induced by an agonist of PKCepsilon (pseudo-receptor octapeptide for activated PKCepsilon) at a dose that itself causes no hyperalgesia. The finding that transient inhibition of PKCepsilon can not only prevent the development of priming, but can also terminate a fully developed state of priming suggests the possibility that selective targeting PKCepsilon might be an effective new strategy in the treatment of chronic inflammatory pain.
最近我们证明，角叉菜胶诱导的单次3天急性皮肤炎症可导致对炎性痛觉过敏易感性增加的慢性状态。在这种潜伏的“致敏”状态下，尽管没有持续的痛觉过敏，但对随后炎性介质（前列腺素E2；PGE2）刺激的痛觉过敏反应会大大增强。此外，在致敏皮肤中，PGE2诱导的痛觉过敏被发现需要蛋白激酶C（PKCε）的ε同工酶的活性，而在对照动物中，PGE2诱导的痛觉过敏不需要这种第二信使。在本研究中，我们检验了以下假设：PKCε的活性不仅在致敏的PGE2诱导的痛觉过敏的表达中起关键作用，而且在致敏状态本身的发展和维持中也起关键作用。采用反义寡脱氧核苷酸使神经中的PKCε减少，通过蛋白质印迹分析进行验证。结果发现，PKCε对角叉菜胶诱导的痛觉过敏致敏的发展以及致敏状态的维持都是必不可少的。此外，PKCε的激动剂（活化PKCε的假受体八肽）在本身不会引起痛觉过敏的剂量下可诱导痛觉过敏致敏。短暂抑制PKCε不仅可以阻止致敏的发展，还可以终止完全发展的致敏状态，这一发现表明，选择性靶向PKCε可能是治疗慢性炎性疼痛的一种有效的新策略。
