There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

中文翻译：

---

半乳糖醛酸-辣椒素前药用于延长伤害性选择性神经阻滞


临床迫切需要开发能够诱导长时间感觉阻滞而不出现肌肉无力或麻痹的神经阻滞剂，以治疗术后和慢性疼痛。在这里，我们报道了一种半乳糖醛酸辣椒素（GalA-CAP）前药作为一种有效的伤害性选择性轴突阻断剂。辣椒素选择性地作用于伤害性信号传导，而不阻断运动神经或破坏本体感觉和触觉，并且半乳糖醛酸部分通过易化葡萄糖转运蛋白（GLUT）介导的转运增强前药穿过限制性周围神经屏障（PNB）的渗透性。此外，在前药跨PNB转运后，无活性的前药通过接头水解转化为活性辣椒素，从而导致药物持续释放。在大鼠坐骨神经处单次注射 GalA-CAP 前药会导致持续 234 ± 37 小时的伤害性选择性神经阻滞，这足以解决术后疼痛最剧烈的时期。此外，该前药显着减轻了辣椒素相关的副作用，从而显着降低了全身毒性、良性局部组织反应以及减少了烧灼和刺激作用。