Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision.
Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision.
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DOI：
10.1016/j.pain.2009.06.037
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发表时间：
2009-10
期刊：
影响因子：
7.4
通讯作者：
Clark DJ
中科院分区：
文献类型：
--
作者：
Sahbaie P;Shi X;Guo TZ;Qiao Y;Yeomans DC;Kingery WS;Clark DJ
P物质（SP）信号促进伤害性敏化在各种炎症和慢性疼痛模型，我们推测，SP信号也可能有助于切口后痛觉过敏的发展。这些研究使用了缺失前速激肽A基因（ppt-A −/−）的小鼠，该基因编码SP，以确定SP信号在切口后疼痛中的作用，以及在切口皮肤中观察到的细胞因子和神经生长因子（NGF）表达增加。与野生型（wt）小鼠相比，SP缺陷型ppt-A（−/−）小鼠在所有切口后时间点均显示出降低的机械异常性疼痛和热痛觉过敏，尽管基线值相似（p<0.001）。此外，NK-1受体拮抗剂LY 303870减弱了野生型小鼠中由切割产生的机械性异常性疼痛（p<0.001）。切口2小时后也上调了wt小鼠皮肤中IL-6、TNF-α和KC的水平，但不上调IL-1β。然而，ppt-A（−/−）小鼠在切口后2小时有更多的皮肤NGF水平。在wt小鼠中，后爪皮下注射SP导致IL-1β、IL-6和KC急性和一过性升高，但TNF-α水平适度升高。全身性LY 303870逆转了SP诱导的这些细胞因子的升高。与野生型小鼠相比，后爪注射IL-6和NGF剂量依赖性地在ppt-A（-/-）小鼠中产生较少的机械性异常性疼痛。此外，SP在野生型小鼠中以剂量依赖性方式产生机械性异常性疼痛。因此，SP支持后爪切口后的伤害性致敏，并可能直接参与调节切口周围组织的炎症反应强度。
Substance P (SP) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia. These studies used mice with a deletion of the pre-protachykinin A gene (ppt-A −/−) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor (NGF) expression observed in the incised skin. SP deficient ppt-A(−/−) mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild type (wt) mice at all post-incision time points, despite similar baseline values (p<0.001). Furthermore, the NK-1 receptor antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice (p<0.001). Incision also up-regulated IL-6, TNF-α and KC levels but not IL-1β after 2 hours in the wt mice skin. However, ppt-A(−/−) mice had more skin NGF levels 2 hours post incision. Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1β, IL-6, and KC but modest elevations in TNF-α levels in the wt mice. Systemic LY303870 reversed the SP induced elevations of these cytokines. Hind paw injection of IL-6 and NGF dose dependently produced less mechanical allodynia in the ppt-A(−/−) compared to wt mice. Additionally, SP produced mechanical allodynia in a dose dependent fashion in wt mice. Therefore, SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue.
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