Ross Jessica L, Queme Luis F, Cohen Elysia R, Green Kathryn J, Lu Peilin, Shank Aaron T, An Suzie, Hudgins Renita C, Jankowski Michael P
Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and.
Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229
J Neurosci. 2016 Jun 29;36(26):6857-71. doi: 10.1523/JNEUROSCI.4582-15.2016.
Musculoskeletal pain is a significantly common clinical complaint. Although it is known that muscles are quite sensitive to alterations in blood flow/oxygenation and a number of muscle pain disorders are based in problems of peripheral perfusion, the mechanisms by which ischemic-like conditions generate myalgia remain unclear. We found, using a multidisciplinary experimental approach, that ischemia and reperfusion injury (I/R) in male Swiss Webster mice altered ongoing and evoked pain-related behaviors in addition to activity levels through enhanced muscle interleukin-1 beta (IL1β)/IL1 receptor signaling to group III/IV muscle afferents. Peripheral sensitization depended on acid-sensing ion channels (ASICs) because treatment of sensory afferents in vitro with IL1β-upregulated ASIC3 in single cells, and nerve-specific knock-down of ASIC3 recapitulated the results of inhibiting the enhanced IL1β/IL1r1 signaling after I/R, which was also found to regulate afferent sensitization and pain-related behaviors. This suggests that targeting muscle IL1β signaling may be a potential analgesic therapy for ischemic myalgia.
Here, we have described a novel pathway whereby increased inflammation within the muscle tissue during ischemia/reperfusion injury sensitizes group III and IV muscle afferents via upregulation of acid-sensing ion channel 3 (ASIC3), leading not only to alterations in mechanical and chemical responsiveness in individual afferents, but also to pain-related behavioral changes. Furthermore, these I/R-induced changes can be prevented using an afferent-specific siRNA knock-down strategy targeting either ASIC3 or the upstream mediator of its expression, interleukin 1 receptor 1. Therefore, this knowledge may contribute to the development of alternative therapeutics for muscle pain and may be especially relevant to pain caused by issues of peripheral circulation, which is commonly observed in disorders such as complex regional pain syndrome, sickle cell anemia, or fibromyalgia.
肌肉骨骼疼痛是一种极为常见的临床症状。尽管已知肌肉对血流/氧合的改变相当敏感，且许多肌肉疼痛疾病都源于外周灌注问题，但类似缺血状态引发肌痛的机制仍不清楚。我们采用多学科实验方法发现，雄性瑞士韦伯斯特小鼠的缺血再灌注损伤（I/R）除了通过增强肌肉白细胞介素-1β（IL1β）/IL1受体信号传导至III/IV组肌肉传入神经来改变活动水平外，还改变了持续的和诱发的疼痛相关行为。外周敏化依赖于酸敏感离子通道（ASICs），因为在体外使用IL1β处理感觉传入神经会使单个细胞中的ASIC3上调，并且ASIC3的神经特异性敲低重现了抑制I/R后增强的IL1β/IL1r1信号传导的结果，这也被发现可调节传入神经敏化和疼痛相关行为。这表明靶向肌肉IL1β信号传导可能是治疗缺血性肌痛的一种潜在镇痛疗法。
在此，我们描述了一种新途径，即缺血/再灌注损伤期间肌肉组织内炎症增加通过上调酸敏感离子通道3（ASIC3）使III和IV组肌肉传入神经致敏，不仅导致单个传入神经的机械和化学反应性改变，还导致疼痛相关的行为变化。此外，使用针对ASIC3或其表达的上游介质白细胞介素1受体1的传入神经特异性siRNA敲低策略可以预防这些I/R诱导的变化。因此，这一知识可能有助于开发治疗肌肉疼痛的替代疗法，并且可能与外周循环问题引起的疼痛特别相关，这种疼痛在复杂区域疼痛综合征、镰状细胞贫血或纤维肌痛等疾病中很常见。
