Burton Michael D, Tillu Dipti V, Mazhar Khadijah, Mejia Galo L, Asiedu Marina N, Inyang Kufreobong, Hughes Travis, Lian Bo, Dussor Gregory, Price Theodore J
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800W. Campbell Rd, Richardson, TX 75080, USA.
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800W. Campbell Rd, Richardson, TX 75080, USA; University of Arizona, Department of Pharmacology, Tucson, AZ 85721, USA.
Neuroscience. 2017 Sep 17;359:119-129. doi: 10.1016/j.neuroscience.2017.07.020. Epub 2017 Jul 17.
New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. Here we have used a variety of administration routes and combinations of AMPK activators to test this hypothesis. Topical administration of a resveratrol-based cream inhibited acute mechanical hypersensitivity evoked by incision and blocked the development of hyperalgesic priming. We also observed that systemic administration of metformin dose-dependently inhibited incision-evoked mechanical hypersensitivity and hyperalgesic priming. Interestingly, low doses of systemic metformin and local resveratrol that had no acute effect were able to mitigate development of hyperalgesic priming. Combined treatment with doses of systemic metformin and local resveratrol that were not effective on their own enhanced the acute efficacy of the individual AMPK activators for post-surgical mechanical pain alleviation and blocked the development of hyperalgesic priming. Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.
需要新的治疗方法来管理术后疼痛，以减轻阿片类药物和其他镇痛药的不良反应。我们之前的研究表明，外周伤害感受器兴奋性的关键调节因子，如细胞外信号调节激酶（ERK），会被单磷酸腺苷激活蛋白激酶（AMPK）的激活所抑制。我们假设，AMPK激活将减轻急性切口诱发的机械性超敏反应以及小鼠手术引起的痛觉过敏预处理的发展。在这里，我们使用了多种给药途径和AMPK激活剂的组合来验证这一假设。局部应用基于白藜芦醇的乳膏可抑制切口诱发的急性机械性超敏反应，并阻止痛觉过敏预处理的发展。我们还观察到，二甲双胍的全身给药剂量依赖性地抑制切口诱发的机械性超敏反应和痛觉过敏预处理。有趣的是，低剂量的全身二甲双胍和局部白藜芦醇本身没有急性作用，但能够减轻痛觉过敏预处理的发展。全身二甲双胍和局部白藜芦醇单独使用无效的剂量联合治疗，增强了个体AMPK激活剂对术后机械性疼痛缓解的急性疗效，并阻止了痛觉过敏预处理的发展。最后，我们使用培养的背根神经节（DRG）神经元表明，联合给予白藜芦醇和二甲双胍可使AMPK激活的浓度-反应曲线向左移动，并增加AMPK激活的幅度。因此，我们发现局部给药是一种有效的给药途径，全身和局部治疗相结合在单独无效的剂量下对急性机械性超敏反应具有抗伤害感受作用。我们的工作共同证明了AMPK激活剂对术后疼痛的特定作用，并指出了在临床环境中具有潜在直接影响的新治疗机会。
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