Pulakat Lakshmi, Sumners Colin
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, United States.
Department of Medicine, Tufts University School of Medicine, Boston, MA, United States.
Front Pharmacol. 2020 Dec 23;11:571994. doi: 10.3389/fphar.2020.571994. eCollection 2020.
Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as 'pain caused by a lesion or disease of the somatosensory nervous system', is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (ATR) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that ATR activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that ATR antagonists are anti-nociceptive and therefore ATR is a drug target for neuropathic pain. However, ATR expression in nociceptive neurons is lacking, indicating that neuronal ATR is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that ATR antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may ATR not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.
对各种急性损伤产生的疼痛可以是一种保护性刺激，以防止机体使用受伤部位，并使组织得以修复和愈合。另一方面，被定义为“由躯体感觉神经系统的损伤或疾病引起的疼痛”的神经性疼痛是一种使人衰弱的病理状态。背根神经节（DRG）中的TRPA1神经元对活性氧（ROS）作出反应并引发疼痛。在急性神经损伤和炎症中，浸润到损伤部位的巨噬细胞会经历氧化爆发，并产生活性氧，这些活性氧促进组织修复并通过TRPA1诱导疼痛。后者会抑制使用受伤肢体，缺乏活动有助于伤口愈合。在由糖尿病、癌症等引起的慢性炎症中，活性氧水平会系统性升高，并调节TRPA1神经元功能，导致使人衰弱的神经性疼痛。在开发用于治疗神经性疼痛的有效药物时，区分引发保护性疼痛与使人衰弱性疼痛的药物靶点非常重要。在这种情况下，2型血管紧张素受体（ATR）与神经性疼痛的关联呈现出一个有趣的困境。几条证据表明，在慢性炎症模型中，ATR激活可促进抗炎和抗伤害感受信号传导、组织修复，并抑制活性氧。相反，一些研究表明，ATR拮抗剂具有抗伤害感受作用，因此ATR是神经性疼痛的药物靶点。然而，伤害性神经元中缺乏ATR表达，这表明神经元ATR不参与神经性疼痛。同样重要的是要考虑到，诺华公司终止了其II期临床试验（EMPHENE），以验证ATR拮抗剂EMA401可减轻带状疱疹后神经痛。该试验于2019年在澳大利亚、英国以及一些欧洲和亚洲国家进行，由于临床前药物毒性数据而中止。此外，该试验的早期数据并未显示出具有统计学意义的阳性结果。这些事实表明，ATR可能不是人类神经性疼痛的合适药物靶点，抑制它可能是有害的。
