Neoinnervation — the growth of new nerve fibers into damaged tendons — driven by upregulated neuropeptides like substance P and CGRP is a key mechanism behind chronic tendon pain.
Substance P + CGRPNeuropeptides consistently upregulated in chronic tendinopathy, driving neoinnervation and pain
What the researchers found
Neuropeptides including substance P and CGRP are consistently upregulated in chronic tendinopathy, with the paratenon serving as a key source of neoinnervation that drives ongoing pain signaling.
Why it matters
Chronic tendon pain affects millions and often responds poorly to treatment. Understanding that new nerve growth — mediated by specific neuropeptides — drives pain opens the door to targeted therapies that address the root cause rather than just masking symptoms.
The numbers in context
- 26 studies reviewed
- 73% (19/26) found neoinnervation in chronic tendinopathy
- 76.9% (20/26) highlighted paratenon role
- 53.8% (14/26) examined both neoinnervation and paratenon
- PGP 9.5 upregulated in 57.6% of studies
- Substance P upregulated in 50% of studies
How the study worked
Scoping review following systematic methodology. Analyzed frequency and progression of neural biomarker upregulation across studies of chronic tendinopathy, with focus on the paratenon's role in neoinnervation.
Who was studied
Scoping review of 26 studies examining neoinnervation in chronic tendinopathy. Included clinical human case-control studies and animal models.
What this study cannot tell us
Scoping review methodology is less rigorous than systematic review with meta-analysis; heterogeneity across included studies in methods and biomarker measurement; mostly observational data without clear causal mechanisms; limited treatment outcome data.
How to read the evidence
Scoping review synthesizing existing evidence. Provides a comprehensive overview but does not generate new primary data or meta-analytic conclusions.
When this study was published
Published in 2025, providing an up-to-date synthesis of the neoinnervation field in tendinopathy.
The bigger picture
This review shifts the understanding of tendinopathy from purely structural damage to a neurovascular process. Targeting neuropeptide-driven neoinnervation could lead to new treatments not just for tendons but for other chronic pain conditions involving aberrant nerve growth.
Questions still open
- Could anti-CGRP therapies already used for migraines be repurposed for chronic tendinopathy?
- Is there a critical window during tendon healing where targeting neoinnervation would be most effective?
- Do different tendon locations show different patterns of neuropeptide upregulation?
Common questions
Why do tendons keep hurting even after they've healed?
What are substance P and CGRP?
Read the original research
Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence - A Scoping Review.
Pain physician, 28(4), 287-297
Citation
Palee, Suwannika; Jarusriwanna, Atthakorn; Lee, Danielle; Yener, Ugur; Kaye, Alan D; Shaparin, Naum; Wahezi, Sayed E. (2025). Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence - A Scoping Review.. Pain physician, 28(4), 287-297.