Chronic pain is a widespread debilitating condition affecting millions of people worldwide. Although several pharmacological treatments for relieving chronic pain have been developed, they require frequent chronic administration and are often associated with severe adverse events, including overdose and addiction. Persistent increased sensitization of neuronal subpopulations of the peripheral and central nervous system has been recognized as a central mechanism mediating chronic pain, suggesting that inhibition of specific neuronal subpopulations might produce antinociceptive effects. We leveraged the neurotoxic properties of the botulinum toxin to specifically silence key pain-processing neurons in the spinal cords of mice. We show that a single intrathecal injection of botulinum toxin conjugates produced long-lasting pain relief in mouse models of inflammatory and neuropathic pain without toxic side effects. Our results suggest that this strategy might be a safe and effective approach for relieving chronic pain while avoiding the adverse events associated with repeated chronic drug administration.

慢性疼痛是一种普遍的使人衰弱的疾病，影响着全世界数百万人。尽管已经开发了几种缓解慢性疼痛的药物治疗，但它们需要频繁的长期给药，并且通常与严重的不良事件有关，包括过量和成瘾。外周和中枢神经系统的神经元亚群的持续增加的敏感性已被认为是介导慢性疼痛的中枢机制，这表明抑制特定的神经元亚群可能会产生镇痛作用。我们利用肉毒杆菌毒素的神经毒性特性来特异性地沉默小鼠脊髓中的关键疼痛处理神经元。我们表明，在炎症性和神经性疼痛的小鼠模型中，单次鞘内注射肉毒杆菌毒素偶联物可产生持久的疼痛缓解，且无毒副作用。我们的研究结果表明，这种策略可能是一种安全有效的缓解慢性疼痛的方法，同时避免了与反复慢性给药相关的不良事件。