Chouhan Deepak, Tiwari Vinod
Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, Uttar Pradesh, India.
Mol Neurobiol. 2025 Apr;62(4):4466-4483. doi: 10.1007/s12035-024-04548-z. Epub 2024 Oct 26.
Burn injury-induced pain (BIP) is a significant global health concern, affecting diverse populations including children, military veterans, and accident victims. Current pharmacotherapeutics for the management of BIP are associated with severe side effects including drug addiction, respiratory depression, sedation, and constipation posing significant barrier to their clinical utility. In the present study, we have investigated the potential role of focal adhesion kinase (p-FAK) for the very first time in BIP and elucidated the associated underlying mechanisms. Defactinib (DFT), a potent p-FAK inhibitor, administered at doses of 5, 10, and 20 mg/kg via intraperitoneal injection, demonstrates significant efficacy in reducing both evoked and spontaneous pain without causing addiction or other central nervous system toxicities. Burn injury triggers p-FAK-mediated phosphorylation of Erk1/2 and NR2B signaling in the DRG, resulting in heightened hypersensitivity through microglial activation, neuropeptide release, and elevated proinflammatory cytokines. Defactinib (DFT) counteracts these effects by reducing NR2B upregulation, lowering substance P levels, inhibiting microglial activation, and restoring IL-10 levels while leaving CGRP levels unchanged. These findings provide valuable insights into the pivotal role of p-FAK in regulating BIP and highlight the potential for developing novel therapeutics for burn injury-induced pain with minimal side effects.
烧伤引起的疼痛（BIP）是一个重大的全球健康问题，影响着包括儿童、退伍军人和事故受害者在内的不同人群。目前用于治疗BIP的药物疗法存在严重的副作用，包括药物成瘾、呼吸抑制、镇静和便秘，这对其临床应用构成了重大障碍。在本研究中，我们首次研究了粘着斑激酶（p-FAK）在BIP中的潜在作用，并阐明了相关的潜在机制。Defactinib（DFT）是一种有效的p-FAK抑制剂，通过腹腔注射以5、10和20mg/kg的剂量给药，在减轻诱发痛和自发痛方面显示出显著疗效，且不会导致成瘾或其他中枢神经系统毒性。烧伤会触发p-FAK介导的背根神经节中Erk1/2和NR2B信号的磷酸化，通过小胶质细胞激活、神经肽释放和促炎细胞因子升高导致超敏反应加剧。Defactinib（DFT）通过降低NR2B上调、降低P物质水平、抑制小胶质细胞激活和恢复IL-10水平来抵消这些影响，同时使降钙素基因相关肽（CGRP）水平保持不变。这些发现为p-FAK在调节BIP中的关键作用提供了有价值的见解，并突出了开发副作用最小的烧伤引起疼痛新型疗法的潜力。
