Quick Q&A
Q: Can past injuries increase sensitivity to future pain or stress?
A: Yes. This research shows that earlier injuries can prime the nervous system to overreact to later stressors, producing prolonged pain and heightened fear even after the wound has healed.
Q: What mechanism keeps the nervous system hypersensitive?
A: A stress hormone called corticosterone works together with the TRPA1 receptor to maintain the nervous system in a danger-ready state, amplifying responses to subsequent threats.
Q: Can fear and chronic pain be separated biologically?
A: Yes. The study found that exaggerated fear requires both TRPA1 and stress hormones, whereas the long-lasting pain depends primarily on stress signaling alone, suggesting different therapeutic targets.
Summary: New research from the University of Toronto demonstrates that healed injuries can leave the nervous system sensitized. In mice, a past injury caused intense fear and renewed pain when they later encountered the scent of a predator, even though no new physical harm occurred.
The study links these persistent effects to corticosterone signaling and the TRPA1 protein, often associated with burning pain. Together, these findings help explain how prior injury or trauma may contribute to chronic pain and trauma-related disorders by keeping the body in a prolonged state of high alert.
Key Facts
- Injury legacy: Past injuries can produce long-term hypersensitivity to stress, fear and pain despite full physical healing.
- Biological loop: Corticosterone and the TRPA1 receptor interact to amplify stress responses and maintain heightened vigilance.
- Separate but related pathways: Fear and persistent pain are mediated by overlapping yet distinct biological mechanisms, creating opportunities for targeted treatments.
Source: University of Toronto
A healed wound can still change how the nervous system responds.
A study published in Current Biology reports that prior injuries can quietly sensitize the nervous system, making animals overreact to later stressors and threats. That heightened sensitivity can manifest as both amplified fear responses and renewed pain, long after the original injury has resolved.
Researchers at the University of Toronto Mississauga used a pain-priming model in mice to examine how a history of injury changes reactions to a psychological danger cue: the scent of a predator. Whereas mice without prior injury showed only brief fear and temporary sensitivity, mice with an injury history displayed exaggerated freezing behavior and prolonged mechanical pain responses in both hind paws, including the uninjured side. Remarkably, these effects persisted for more than six months after the injury had healed.
“Our brains are designed to protect us from threats,” said Dr. Loren Martin, associate professor of psychology and senior author of the study. “But that protective state can stay engaged after the danger is gone, leaving people overly sensitive to stress and pain. Understanding how past injuries reshape the brain may help us develop better treatments for chronic pain and anxiety disorders.”
Graduate student Jennet Baumbach, first author of the paper, identified a critical interaction linking stress to long-lasting pain. She found that corticosterone, a key stress hormone in rodents, acts through the TRPA1 receptor—a protein often called the “wasabi” receptor because its activation produces a burning sensation—to sensitize responses to future threats. This corticosterone–TRPA1 signaling loop appears to maintain the nervous system in a heightened state, so that a predator odor triggers both renewed pain and increased fear even without new tissue damage.
Importantly, the researchers showed that both TRPA1 activity and corticosterone were necessary for the amplified fear response. However, the persistent mechanical pain depended mainly on stress hormone signaling and did not require TRPA1. That distinction indicates that fear and chronic pain involve overlapping but separable biological circuits, with implications for treatment: blocking stress signaling might relieve ongoing pain, while targeting TRPA1 could reduce extreme fear reactions tied to prior injury.
Pharmacological experiments supported these conclusions. In pain-primed mice, inhibiting corticosterone synthesis prevented exaggerated freezing and reversed long-lasting mechanical hypersensitivity. Antagonizing TRPA1 suppressed the corticosterone surge and reduced freezing behavior, but did not block the prolonged pain, reinforcing the idea of dual mechanisms for fear and pain maintenance.
“We are dissecting the central circuits that control these behaviors,” Dr. Martin said. “Pinpointing how trauma rewires stress and pain pathways will let us target the specific processes that keep fear and pain locked in place.” These insights could inform new therapies for chronic pain, post-traumatic stress disorder (PTSD), and other conditions where stress and pain persist beyond the original injury.
About this PTSD and neuroscience research news
Author: Julia Le
Source: University of Toronto
Contact: Julia Le, University of Toronto
Image: Image credited to Neuroscience News
Original Research: Open access. “A history of injury enhances affective and sensory responses to predator threat by sensitizing corticosterone release through TRPA1 receptor signaling” by Loren Martin et al., Current Biology. DOI: 10.1016/j.cub.2025.07.005
Abstract
A history of injury enhances affective and sensory responses to predator threat by sensitizing corticosterone release through TRPA1 receptor signaling
Detecting pain and danger cues based on past experience is an essential adaptive behavior. It allows organisms to recognize, learn, and remember threats so they can react rapidly and appropriately. In injured animals, heightened pain sensitivity increases vigilance and improves the chance of responding to environmental threats.
Previous studies have examined neuronal pain memory and priming, where a strong noxious event increases responsiveness to later mild stimuli. However, less is known about how earlier pain shapes responses to psychological danger cues and the underlying physiology. Using a pain-priming model, this study tested how a history of injury alters reactions to predator odor (trimethylthiazoline, TMT).
In naive mice, TMT produced short-lived fear and transient mechanical hypersensitivity. In contrast, pain-primed mice showed amplified freezing and prolonged mechanical hypersensitivity lasting more than six months. These persistent responses required corticosterone signaling during TMT exposure: blocking corticosterone synthesis prevented freezing and reversed mechanical hypersensitivity in pain-primed mice. TRPA1 antagonism reduced corticosterone elevation and freezing, implicating the TRPA1–stress axis in fear amplification. However, TRPA1 antagonism did not prevent the prolonged mechanical hypersensitivity, indicating that fear and sustained pain after injury are mediated by distinct pharmacological mechanisms.
Overall, the findings show that pain priming sensitizes the TRPA1–stress pathway and reconfigures stress and pain circuits, increasing vulnerability to future threats and offering potential targets for interventions in chronic pain and stress-related disorders.