Low-Level Laser Therapy Relieves Chronic Muscle Pain by Activating Substance P's Pain-Relieving Role | Research

The takeaway

Low-level laser therapy reduces chronic muscle pain through an unexpected antinociceptive role of intramuscular Substance P signaling via NK1 receptors and TRPV1 activation in a fibromyalgia mouse model.

Pain relief abolished
Both NK1R antagonist treatment and Substance P gene deletion completely eliminated LLLT's analgesic effect, proving Substance P mediates laser therapy pain relief

What the researchers found

LLLT with 685 nm at 8 J/cm² effectively reduced mechanical hyperalgesia in the acid-induced chronic muscle pain (fibromyalgia) model. The analgesic effect was completely abolished by: (1) pretreatment with NK1 receptor antagonist RP-67580, (2) deletion of the Tac1 gene encoding Substance P (Tac1-/- mice), and (3) pretreatment with TRPV1 antagonist capsazepine. However, ASIC3 antagonist APETx2 did not block the effect.

This demonstrates that LLLT analgesia is mediated by intramuscular Substance P's antinociceptive (pain-reducing) signaling through NK1 receptors and involves TRPV1 activation — revealing an unexpected pain-relieving role for a neuropeptide traditionally associated with pain promotion.

Why it matters

LLLT is widely used for pain management but its mechanism has been poorly understood, limiting its acceptance and optimization. This study provides a specific molecular mechanism — Substance P acting in its paradoxical anti-pain role — that could guide more effective LLLT protocols. It also changes how we think about Substance P: rather than being exclusively pro-pain, it can also suppress pain depending on the context and location.

How the study worked

Researchers used the acid-induced chronic muscle pain model (a validated fibromyalgia model) in C57BL mice. Optimal LLLT dosage (685 nm, 8 J/cm²) was determined. Pharmacological interventions included NK1R antagonist (RP-67580), TRPV1 antagonist (capsazepine), and ASIC3 antagonist (APETx2). Genetic validation used Tac1 knockout mice lacking the Substance P gene. Mechanical hyperalgesia was assessed as the primary outcome.

What this study cannot tell us

The study was conducted in mice using a chemical pain model; translation to human fibromyalgia may differ. Only one laser wavelength and dosage was tested. The mechanism by which LLLT activates intramuscular Substance P release was not determined. Whether this antinociceptive role of Substance P applies to other chronic pain conditions beyond the muscle pain model is unknown.

How to read the evidence

This is a preclinical animal study using pharmacological and genetic approaches to establish a causal mechanism. The use of both antagonist blockade and knockout mice provides strong converging evidence for the role of Substance P, though results are from a mouse model only.

When this study was published

Published in 2019, this study provides important mechanistic insight into how LLLT works at the neuropeptide level, informing both clinical LLLT practice and our understanding of Substance P biology.

The bigger picture

This study reveals a dual nature of Substance P in pain processing: while it promotes pain signaling in the spinal cord, it can mediate pain relief when activated in peripheral muscle tissue. This context-dependent function of a single neuropeptide underscores the complexity of peptide signaling and suggests that therapies targeting Substance P may have different effects depending on where and how they act.

Questions still open

What determines whether Substance P promotes or inhibits pain in different tissues and contexts?
Could optimizing LLLT parameters based on Substance P signaling dynamics improve pain relief outcomes in fibromyalgia patients?
Do NK1R antagonists developed for other conditions inadvertently block the beneficial effects of LLLT on pain?

Common questions

Can Substance P both cause and relieve pain?

Yes — this is a key finding. In the spinal cord, Substance P transmits pain signals from the body to the brain. But in muscle tissue, this study shows it can have the opposite effect — actually reducing pain when activated by laser therapy. This dual role depends on where the neuropeptide acts and the specific context of its release.

How does low-level laser therapy reduce pain?

According to this study, the laser activates TRPV1 receptors in muscle tissue, which triggers the release of Substance P locally in the muscle. In this peripheral location, Substance P acts through NK1 receptors to produce pain relief — opposite to its pain-promoting role in the spinal cord. This explains why laser therapy is effective for conditions like fibromyalgia.

Read the original research

Involvement of Substance P in the Analgesic Effect of Low-Level Laser Therapy in a Mouse Model of Chronic Widespread Muscle Pain.

Pain medicine (Malden, Mass.), 20(10), 1963-1970

View on PubMed ↗Publisher’s paper ↗

Citation

Han, Der-Sheng; Lee, Cheng-Han; Shieh, Yih-Dar; Chen, Chih-Cheng. (2019). Involvement of Substance P in the Analgesic Effect of Low-Level Laser Therapy in a Mouse Model of Chronic Widespread Muscle Pain.. Pain medicine (Malden, Mass.), 20(10), 1963-1970. https://doi.org/10.1093/pm/pnz056