Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury.
Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury.
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DOI：
10.1177/1744806918788648
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发表时间：
2018-01
期刊：
影响因子：
3.3
通讯作者：
Tan AM
中科院分区：
文献类型：
--
作者：
Guo Y;Benson C;Hill M;Henry S;Effraim P;Waxman SG;Dib-Hajj S;Tan AM
痛苦的烧伤是最使人衰弱的创伤形式之一，在全球排名前15位的慢性疾病负担的主要原因。然而，尽管烧伤后慢性疼痛很普遍，但对它的研究还不够深入。我们之前证明了rac1信号通路在包括烧伤在内的几种神经病理性疼痛模型中的作用。然而，由于其复杂的细胞内动力学，rac1属于一类治疗作用较低的GTP酶。为了进一步了解烧伤诱发神经病理性疼痛的机制基础，我们进行了一项纵向研究，以解决以下假设：抑制rac1下游效应器pak1将改善二度烧伤后的疼痛结局。大量证据表明，PAK1有望成为认知功能障碍的临床靶点，也是许多神经系统疾病所致树突棘发育不全所必需的。在我们的烧伤模型中，小鼠表现出明显的触觉过敏、热痛觉过敏和背角树突棘发育不良。C-fos的活性依赖性表达在背角神经元中也增加，这是中枢伤害性活动增强的指标。为了抑制pak1，我们改变了FDA批准的抑制剂romidessin的用途。罗米地平治疗减少了树突棘发育不良，减少了c-fos的表达，并挽救了痛觉阈值。停药会导致疼痛的细胞相关性复发，并导致行为测试中的痛阈值降低。综上所述，我们的研究结果表明，pak1信号是治疗创伤性烧伤所致神经病理性疼痛的潜在分子靶点。
Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury. However, Rac1 belongs to a class of GTPases with low therapeutic utility due to their complex intracellular dynamics. To further understand the mechanistic underpinnings of burn-induced neuropathic pain, we performed a longitudinal study to address the hypothesis that inhibition of the downstream effector of Rac1, Pak1, will improve pain outcome following a second-degree burn injury. Substantial evidence has identified Pak1 as promising a clinical target in cognitive dysfunction and is required for dendritic spine dysgenesis associated with many neurological diseases. In our burn injury model, mice exhibited significant tactile allodynia and heat hyperalgesia and dendritic spine dysgenesis in the dorsal horn. Activity-dependent expression of c-fos also increased in dorsal horn neurons, an indicator of elevated central nociceptive activity. To inhibit Pak1, we repurposed an FDA-approved inhibitor, romidepsin. Treatment with romidepsin decreased dendritic spine dysgenesis, reduced c-fos expression, and rescued pain thresholds. Drug discontinuation resulted in a relapse of cellular correlates of pain and in lower pain thresholds in behavioral tests. Taken together, our findings identify Pak1 signaling as a potential molecular target for therapeutic intervention in traumatic burn-induced neuropathic pain.