Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury

Lihui Li; Hongyu Yao; Rufan Mo; Lihong Xu; Peng Chen; Yuchen Chen; Jiang-Jian Hu; Wei Xie; Xue-Jun Song

doi:10.1097/j.pain.0000000000003229

Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury

Pain. 2024 Apr 9. doi: 10.1097/j.pain.0000000000003229. Online ahead of print.

Authors

Lihui Li^{1

2}, Hongyu Yao^{1

2}, Rufan Mo², Lihong Xu¹, Peng Chen^{1

2}, Yuchen Chen¹, Jiang-Jian Hu^{1

2}, Wei Xie³, Xue-Jun Song^{1

2}

Affiliations

¹ Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
² SUSTech Center for Pain Medicine, Southern University of Science and Technology, Shenzhen, China.
³ The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, The School of Life Science and Technology, Southeast University, Nanjing, China.

PMID: 38598349
DOI: 10.1097/j.pain.0000000000003229

Abstract

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.