Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.

中文翻译：

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阻断蛋白酶激活受体 2 信号传导可缓解跟腱损伤大鼠的疼痛、抑制神经萌芽、改善组织修复并增强 B 族维生素的镇痛效果。

肌腱损伤会产生顽固性疼痛和运动障碍，但镇痛和恢复肌腱功能完整性的药物仍然有限。在这项研究中，我们报告背根神经节（DRG）神经元中蛋白酶激活受体2（PAR2）的激活导致跟腱部分横断损伤（TTI）产生的慢性疼痛和肌腱组织病理学变化。肌腱部分横断损伤增加了受损跟腱内 DRG 神经元体及其周围末梢 PAR2 蛋白的表达。 PAR2 的激活通过激活下游 cAMP-PKA 通路以及 PKC、CaMKII 和 CREB ​​的磷酸化来促进初级感觉神经元的可塑性。通过 PAR2 小干扰 RNA 或拮抗肽 PIP 阻断 PAR2 信号传导可延迟 TTI 诱导的疼痛的发作，逆转持续的疼痛，并抑制感觉神经萌芽，并促进受损肌腱的结构重塑。维生素 B 复合物 (VBC) 含有硫胺素 (B1)、吡哆醇 (B6) 和氰钴胺 (B12)，可通过抑制 PAR2 激活有效改善 TTI 引起的疼痛、抑制异位神经萌芽并加速肌腱修复。这些发现揭示了 PAR2 信号传导在跟腱损伤后慢性疼痛的发展和受伤肌腱的组织病理学改变中的关键作用。这项研究表明，针对 PAR2 的药物，如 VBC，可能是治疗肌腱损伤引起的疼痛和促进肌腱修复的有效方法。