99: C-fiber infiltration into damaged tissues in rat models of bone cancer and Achilles tendon injury

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Pharmacological interventions

Background and Aims: Bone cancer and severe tendon injury can cause persistent pain. The underlying mechanisms for such painful conditions are elusive and the treatment approaches for pain relief remain limited. In this study, we investigated the peripheral neural mechanisms underlying chronic pain in tumor cell implantation (TCI) model, producing cancer pain, and the Achilles tendon partial transection injury (TTI) model, producing tendon injury pain, as well as exploring pain relief approaches.

Methods: Experiments were performed on adult male Sprague‑Dawley rats. Two clinically relevant chronic pain models were established, in the tumor cell implantation (TCI) model, cancer pain was induced by implanting tumor cells into the tibia. In the Achilles tendon partial transection injury (TTI) model, tendon injury pain was produced by partial transection of the Achilles tendon. The painful behavior tests and the techniques of DiI retrograde tracing, H&E staining, RNAScope, immunofluorescence, and Western Blot were employed in the experiments.

Results: We characterized ectopic sensory nerve innervation in cancer-invaded bone and injured tendon and analyzed alterations of molecules related with sensory nerve remodeling. Our results showed that both TCI and TTI increased the abundance of nociceptor innervation in cancer-invaded bone and injured tendon tissue. We identified that the proteinase-activated receptor 2 (PAR2) was upregulated in the dorsal root ganglion (DRG) soma and peripheral terminals following TCI or TTI. Upregulation of PAR2 increased plasticity of DRG nociceptors through activating cAMP/PKA signaling and promoting phosphorylation of PKC, CaMKII, and CREB. Pharmacological or genetic perturbation of PAR2 in DRG reduced the ectopic sensory nerve innervation and ameliorated pain after TCI and TTI. Systemic administration of vitamin B complex comprising thiamine, pyridoxine, and cyanocobalamin produced significant analgesic effects and suppressed ectopic sensory nerve innervation by blocking PAR2 activation. Part of these data have been published in our recent papers.

Conclusions: Our study supports the idea that PAR2 is critical to the ectopic sensory nerve innervation during the development of chronic pain following bone cancer or tendon injury; targeting PAR2, for instance with VBC, is a promising therapeutic strategy for pain management after bone cancer or tendon injury.

References: 1. Zhai, M.Z. et al. Wnt5a/Ryk signaling contributes to bone cancer pain by sensitizing the peripheral nociceptors through JNK-mediated TRPV1 pathway in rats. Pain 2025,166(3): 680-692.
2. Li, L.H. et al. 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 2024,165(9): 2055-2067.

Presenting Author: Xue-Jun Song
Submitting Author: Xue-Jun Song

Senior Author: Xue-Jun Song

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Peng Chen - Department of Medical Neuroscience and SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
• Mingzhu Zhai - Department of Medical Neuroscience and SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China
• Lihui Li - Department of Medical Neuroscience and SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China
• Hongyu Yao - Department of Medical Neuroscience and SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
• Xue-Jun Song - Department of Medical Neuroscience and SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, China