Neuropeptides Play a Key Role in Chronic Tendon Pain Through New Nerve Growth
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.
Quick Facts
What This Study 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.
Key Numbers
- 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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Substance P + CGRP Neuropeptides consistently upregulated in chronic tendinopathy, driving neoinnervation and pain
- Evidence Grade:
- Scoping review synthesizing existing evidence. Provides a comprehensive overview but does not generate new primary data or meta-analytic conclusions.
- Study Age:
- Published in 2025, providing an up-to-date synthesis of the neoinnervation field in tendinopathy.
- Original Title:
- Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence - A Scoping Review.
- Published In:
- Pain physician, 28(4), 287-297 (2025)
- Authors:
- Palee, Suwannika, Jarusriwanna, Atthakorn, Lee, Danielle, Yener, Ugur, Kaye, Alan D, Shaparin, Naum, Wahezi, Sayed E
- Database ID:
- RPEP-12924
Evidence Hierarchy
Maps out the available research on a broad question.
What do these levels mean? →Frequently Asked Questions
Why do tendons keep hurting even after they've healed?
This review shows that damaged tendons can grow new nerve fibers (neoinnervation) that weren't there before. These new nerves, driven by neuropeptides like substance P, keep sending pain signals even after the structural damage has resolved.
What are substance P and CGRP?
They are neuropeptides — small signaling molecules released by nerve cells. Substance P transmits pain signals, while CGRP dilates blood vessels and promotes inflammation. Both are elevated in chronically painful tendons and contribute to ongoing pain.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-12924APA
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.
MLA
Palee, Suwannika, et al. "Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence - A Scoping Review.." Pain physician, 2025.
RethinkPeptides
RethinkPeptides Research Database. "Chronic Tendinopathy Driven by Neoinnervation: The Role of t..." RPEP-12924. Retrieved from https://rethinkpeptides.com/research/palee-2025-chronic-tendinopathy-driven-by
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.