Could a Pain Molecule Help Drive Tendon Degeneration?

We generally think of tendon degeneration as a response to excessive mechanical loading.

Repetitive stress alters cellular behavior, disrupts matrix homeostasis, and eventually produces the structural abnormalities we recognize as tendinopathy.

But what if a molecule we typically associate with pain also helps drive those changes?

Substance P.

A neuropeptide best known for its role in sensory signaling.

Yet human tendon cells can produce it themselves. And experimental research suggests it may contribute to some of the tissue changes we associate with tendinopathy.

The tendon produces its own neuropeptides

Substance P is commonly associated with sensory nerves, inflammation, and nociceptive signaling.

But tenocytes can produce substance P in response to mechanical loading.

In a 2011 study, researchers subjected cultured human Achilles tenocytes to repetitive mechanical strain. Substance P gene expression increased more than fourfold.

Even more interestingly, substance P stimulated tenocyte proliferation through neurokinin-1 receptors, suggesting that tendon cells can both produce and respond to this signaling molecule. Backman et al., 2011​

And its effects extend beyond cellular proliferation.

In another experiment, substance P increased collagen remodeling and MMP-3 expression in cultured human tenocytes. Mechanical loading further enhanced this response. Fong et al., 2013​

The tendon isn't simply responding to neural signals. Its own cells can generate signals that influence tissue remodeling.

Could substance P actually promote tendinopathy?

The animal data make this question particularly interesting.

In a rabbit model of Achilles overuse, researchers administered substance P locally during repetitive loading.

After one week, the substance P group demonstrated greater vascular proliferation and paratendinous inflammation than saline-injected controls. Tendon cellularity was also increased relative to uninjected controls, although not significantly greater than in the saline-injected group.

These findings suggest that substance P can accelerate certain tendinosis-like changes under experimental conditions. Andersson et al., 2011​

Consider the implications.

A molecule we commonly associate with pain signaling may also influence the cellular and vascular changes that characterize diseased tendons.

What if some of the neurochemical changes observed in tendinopathy aren't simply consequences of tissue degeneration, but active contributors to its development?

There is an important distinction here.

Substance P isn't inherently pathological. It also participates in normal tissue adaptation and repair. And these laboratory and animal findings don't establish that substance P causes chronic tendinopathy in humans.

But they suggest that the relationship between mechanical loading, neural signaling, and tendon remodeling may be more interconnected than we often appreciate.

The MSK Logic

We typically approach tendinopathy by trying to restore the tendon's ability to tolerate mechanical load.

That remains fundamental.

But the structural abnormalities we see on imaging may reflect a complex interaction between mechanical forces, cellular signaling, vascular changes, and extracellular matrix remodeling.

Mechanical loading can influence neuropeptide production. Those neuropeptides can influence tendon-cell behavior. And the resulting tissue changes may alter how the tendon responds to future loading.

Perhaps the abnormal signaling we associate with tendon degeneration isn't always a consequence of the pathology. Sometimes, it may be part of what drives it.

When we treat tendinopathy, we may be treating an ecosystem, not just a tendon.