Substance P and Its Receptor Drive Central Sensitization in Chronic Pain | Research

The takeaway

The substance P/NK1 receptor system is involved in central sensitization — a key mechanism of chronic pain — with evidence from nerve injury mouse models showing its role in maintaining persistent pain.

30%+ affected worldwide
Chronic pain driven partly by substance P/NK1R-mediated central sensitization

What the researchers found

The substance P/NK1R system is involved in central sensitization in chronic pain, as demonstrated in a spared nerve injury mouse model.

Why it matters

Despite decades of research, effective treatments for chronic pain remain elusive. Clarifying substance P's role in central sensitization could revive interest in NK1R antagonists or related drug targets.

How the study worked

Preclinical study using spared nerve injury (SNI) mouse model with behavioral, molecular, and pharmacological analysis of substance P/NK1R system.

What this study cannot tell us

Mouse model may not fully replicate human chronic pain; SNI represents neuropathic pain specifically; NK1R antagonists have previously failed in human pain trials.

How to read the evidence

Preclinical mouse study — provides mechanistic evidence but translational relevance to human chronic pain needs validation.

When this study was published

Published in 2026, re-examining a classic neuropeptide target with modern techniques.

The bigger picture

Substance P was once a major drug target for pain, but NK1R antagonists largely failed in clinical trials. This new evidence of its role in central sensitization could lead to more targeted approaches that succeed where earlier drugs failed.

Questions still open

Could next-generation NK1R antagonists targeting central sensitization specifically succeed where earlier drugs failed?
Is substance P's role in central sensitization different from its role in acute pain transmission?

Common questions

What is central sensitization?

Central sensitization is when the nervous system becomes hypersensitive to pain, amplifying signals so that normal touch can feel painful and minor injuries cause severe pain. It's a major driver of chronic pain conditions.

What is substance P?

Substance P is a neuropeptide (small protein) released by nerve cells that transmits pain signals. It binds to NK1 receptors and has been studied for decades as a potential target for pain treatment.

Read the original research

Involvement of substance P/NK1 receptor system in central sensitization in chronic pain.

Neuroscience letters, 871, 138464

View on PubMed ↗Publisher’s paper ↗

Citation

Chen, Juan; Lai, Yimin; Li, Wei. (2026). Involvement of substance P/NK1 receptor system in central sensitization in chronic pain.. Neuroscience letters, 871, 138464. https://doi.org/10.1016/j.neulet.2025.138464