短链小干扰 RNA 产生干扰素-α介导的镇痛作用。
Short small-interfering RNAs produce interferon-α-mediated analgesia.
机构信息
Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
出版信息
Br J Anaesth. 2012 Apr;108(4):662-9. doi: 10.1093/bja/aer492. Epub 2012 Feb 3.
BACKGROUND
There is increasing interest in RNA interference in pain research using the intrathecal route to deliver small-interfering RNA (siRNA). An interferon (IFN) response is a common side-effect of siRNA. However, the IFN response in the spinal cord after intrathecal administration of siRNA remains unknown. We hypothesized that high doses of siRNAs can elicit off-target analgesia via releasing IFN-α. We investigated the IFN response and its role in regulating pain sensitivity in the spinal cords after intrathecal administration of siRNAs.
METHODS
Male Sprague-Dawley rats were given intrathecal injections of non-targeting (NT) siRNAs or IFN-α and tested for complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. IFN-α in the spinal cord after injection of NT siRNAs was measured by western blotting and immunohistochemical staining.
RESULTS
IFN-α was up-regulated in the spinal cord after intrathecal treatment of NT siRNAs. Intrathecal injection of NT siRNAs, at high doses of 10 or 20 μg, reduced CFA-induced inflammatory pain (P<0.05). Intrathecal application of IFN-α inhibited pain hypersensitivity in inflamed rats and produced analgesia in naïve rats (P<0.05). Notably, the anti-nociceptive effects elicited by NT siRNAs and IFN-α were reversed by IFN-α neutralizing antibody and naloxone.
CONCLUSIONS
Our data suggest that (i) intrathecal administration of high doses of siRNA (≥ 10 μg) induced up-regulation of IFN-α in the spinal cord and produced analgesic effects through IFN-α, and (ii) IFN-α's analgesic effect is mediated via opioid receptors. Caution must be taken to avoid IFN-α-mediated analgesic effects of siRNAs in pain research.
背景
利用鞘内途径递送小干扰 RNA（siRNA）进行疼痛研究，RNA 干扰技术的应用日益受到关注。干扰素（IFN）反应是 siRNA 的常见副作用。然而，鞘内给予 siRNA 后脊髓中的 IFN 反应尚不清楚。我们假设高剂量的 siRNA 可以通过释放 IFN-α 产生脱靶镇痛作用。我们研究了鞘内给予 siRNA 后脊髓中的 IFN 反应及其在调节疼痛敏感性中的作用。
方法
雄性 Sprague-Dawley 大鼠给予鞘内注射非靶向（NT）siRNA 或 IFN-α，并进行完全弗氏佐剂（CFA）诱导的机械性痛觉过敏和热痛觉过敏测试。通过 Western 印迹和免疫组织化学染色测量注射 NT siRNA 后脊髓中的 IFN-α。
结果
鞘内给予 NT siRNA 后，脊髓中 IFN-α 上调。鞘内给予高剂量 10 或 20 μg 的 NT siRNA 可减轻 CFA 诱导的炎症性疼痛（P<0.05）。鞘内给予 IFN-α 抑制炎性大鼠的痛觉过敏，并在正常大鼠中产生镇痛作用（P<0.05）。值得注意的是，NT siRNA 和 IFN-α 引起的抗伤害感受作用被 IFN-α 中和抗体和纳洛酮逆转。
结论
我们的数据表明：（i）鞘内给予高剂量的 siRNA（≥10 μg）可诱导脊髓中 IFN-α 的上调，并通过 IFN-α 产生镇痛作用；（ii）IFN-α 的镇痛作用是通过阿片受体介导的。在疼痛研究中，必须谨慎避免 siRNA 介导的 IFN-α 镇痛作用。
Zotero 插件