Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States.
Translational and Comparative Medical Research, Elanco Animal Health, Greenfield, IN, United States.
Pain. 2018 Oct;159(10):2105-2114. doi: 10.1097/j.pain.0000000000001314.
The translational potential of analgesic approaches emerging from basic research can be augmented by client-owned dog trials. We report on a peripheral interventional approach that uses intra-articular injection of the ultrapotent TRPV1 agonist resiniferatoxin (RTX) to produce a selective long-term chemoinactivation of nociceptive primary afferent nerve endings for pain control in naturally occurring canine osteoarthritis. A single injection of 10 µg of RTX, produced suppression of pain, improvement in gait, weight bearing, and improvement in the dog's activities of daily living lasting 4 months or longer. Two to 3 years after the injection, there are no alterations to suggest that removal of inflammatory pain caused accelerated joint degeneration (Charcot joint) in any of the dogs. To amplify the effective use of canine subjects in translational analgesia research, we report a high-quality canine dorsal root ganglion transcriptome. Some targets for analgesia are highly conserved both in protein sequence and level of expression within a target tissue while others diverge substantially from the human. This knowledge is especially important for development of analgesics aimed at peripheral molecular targets and provides a template for informed translational research. The peripheral site of action, long duration of analgesia, apparent safety, and retention of coordination, all resulting from a single dose suggest that intra-articular RTX may be an effective intervention for osteoarthritis pain with few or no side effects and lead to an improved quality of life.
从基础研究中出现的镇痛方法的转化潜力可以通过客户拥有的狗试验来增强。我们报告了一种外周介入方法，该方法使用关节内注射超效 TRPV1 激动剂树脂毒素 (RTX) 来选择性地长期化学失活伤害感受初级传入神经末梢，以控制犬自然发生的骨关节炎疼痛。单次注射 10µg RTX 可抑制疼痛、改善步态、负重和犬的日常生活活动，持续 4 个月或更长时间。在注射后 2 至 3 年，没有任何迹象表明消除炎症性疼痛会加速任何一只狗的关节退化（夏科关节）。为了放大犬科动物在转化镇痛研究中的有效利用，我们报告了高质量的犬背根神经节转录组。一些镇痛靶点在蛋白质序列和靶组织表达水平上具有高度保守性，而另一些则与人类有很大差异。这一知识对于针对外周分子靶点开发镇痛药尤为重要，并为知情的转化研究提供了模板。关节内 RTX 的作用部位在外周、镇痛持续时间长、安全性高、协调性保持不变，所有这些都来自单次剂量，这表明关节内 RTX 可能是一种有效的骨关节炎疼痛干预措施，副作用很少或没有，从而提高生活质量。
