Memories of past injuries amplify future fear and pain responses in the brain

Past injuries fade from sight, yet the memory of them lingers in the nervous system. A new mouse study shows a single inflammatory injury can keep the brain on high alert, amplifying fear and pain for months.

A recent study reveals how stress hormones and a sensory protein keep the harm alarm ringing. Dr. Loren Martin and colleagues at the University of Toronto Mississauga led the work, showing why some people stay hypersensitive to previous injuries, long after a wound mends.

Memory of old injuries reshapes circuits

Most of us assume pain stops when tissues heal, but clinical data suggest otherwise. Children exposed to injury or adversity have a higher likelihood of adult chronic pain and anxiety disorders.

“Our brains are wired to protect us , especially from threatening situations,” said Dr. Martin. The team paired healed mice with trimethylthiazoline, a fox odor chemical that rodents innately fear, and naive animals froze briefly, then moved on. 

These findings echo human reports where pre-trauma pain experience predicts persistent pain after car crashes or combat. The data strengthen the idea that injury history reshapes defensive circuits, setting a lower threshold for danger.

Hormones in the driver’s seat

The hormone corticosterone is the rodent equivalent of cortisol: it is released when the stress axis fires. Elevating corticosterone for weeks can induce anxiety-like behavior in healthy mice.

Healed mice released a larger corticosterone surge when they smelled predator odor compared with controls. Blocking hormone synthesis during the odor challenge prevented both the prolonged paw pain and the extended freezing.

Imaging studies show cortisol spikes strengthen connections between the amygdala and pain processing regions, making future stressors feel more intense. The mouse data supply a mechanistic foothold and hint that dampening glucocorticoid swings might calm runaway pain in trauma survivors.

The wasabi receptor’s surprising cameo

Enter TRPA1, sometimes dubbed the “wasabi receptor” because it fires in response to pungent compounds. Beyond the sinuses, TRPA1 sits on sensory neurons and contributes to inflammatory pain.

Pharmacological TRPA1 blockade during predator odor exposure normalized corticosterone release and curtailed freezing. Yet the same blockade failed to stop the long term paw hypersensitivity, revealing a split between fear and pain pathways.

TRPA1’s involvement in threat sensing makes evolutionary sense since it serves as a chemical early warning system. In healed mice, that detector seems recalibrated to overshoot, sounding the alarm even when no fresh injury exists.

Fear and pain are separate roads

Researchers often lump fear and pain together because they co-occur, but Martin’s data tell a different story. Inhibiting corticosterone abolished both paths, while inhibiting TRPA1 trimmed only the fear branch.

A dynamical systems model published last year supports partially overlapping neural hubs rather than a single circuit. Decoupling the roads matters for treatment because drugs that calm fear might leave pain untouched and vice versa.

Clinicians therefore need to screen both domains separately instead of assuming progress in one guarantees relief in the other. Such tailored assessments could speed patients toward the right mix of therapies.

Memory of injury alters brain connectivity

New research suggests that pain priming may not just affect immediate sensory responses but also alter long-term memory encoding of threat cues. This could explain why even subtle reminders of past trauma can trigger both emotional distress and physical symptoms in people with a history of injury or adversity.

Studies using imaging techniques have shown that chronic pain alters connectivity in brain regions like the hippocampus, which plays a key role in memory formation. If injury history reshapes how threats are stored and retrieved, it may be possible to develop therapies that weaken the emotional and physical recall of danger signals.

What it means for people in pain

Roughly one in five U.S. adults lives with chronic pain. The mouse findings suggest that an early stressor, even psychological, can cement pain circuits irrespective of lingering inflammation.

That insight reframes conditions like fibromyalgia, where hypersensitivity spreads beyond the original injury. If similar hormone sensor loops operate in humans, targeting them could spare patients years of trial and error painkillers.

The work also hints at a biological link between chronic pain and anxiety diagnoses that often coexist in clinics. Shared stress hormone circuits may explain why treating one symptom eases the other.

Can the injury-memory link be treated?

Corticosteroid synthesis inhibitors already exist for endocrine disorders and might merit short, time limited trials after severe injury to test whether they blunt later pain. Selective TRPA1 antagonists have reached early phase safety testing for asthma and cough, proving they can be taken systemically without major side effects. 

The strategy would be brief, given corticosterone’s vital role in metabolism. Delivering inhibitors only during the immediate stress window could prevent sensitization without hampering long term healing.

Questions that remain

Do the same pathways hold in female mice and older animals? Hormone cycles and aging both alter glucocorticoid dynamics, and chronic pain is more common in women.

Another open question is whether the intervention window closes quickly or stays open for weeks. If sensitization hardens within days, emergency department protocols after injuries might need to incorporate stress hormone management before patients even go home.

The study is published in Current Biology.

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