Past injuries heighten fear, pain in stressful situations, study indicates

Old injuries can heighten the body’s fear and pain responses in stressful situations – even long after the initial wound has healed, new research from the University of Toronto Mississauga suggests.

Those findings, along with insight into the biological underpinnings of such responses, could lead to better treatments for chronic pain conditions, the researchers say in a study recently published in the journal Current Biology.

“Our results reveal that a history of pain reconfigures stress and pain circuits in the nervous system, which creates a sort of hypervigilance to future threats,” says Jennet Baumbach, first author of the study and a doctoral student in the lab of senior author Loren Martin, an associate professor in UTM’s department of psychological and brain sciences.

The study saw researchers expose mice with a past foot injury to a highly stressful event: the scent of a predator. The mice, compared to those without an injury, had higher stress hormone levels and showed increased fear-induced freezing behaviour as well as hypersensitivity to pain for much longer – up to six months, as opposed to a day or two. The injured mice also exhibited hypersensitivity in both paws, not just the one that had been hurt.  

Other research has demonstrated that previous physical pain intensifies responses to subsequent physical pain in the same part of the body, but this study was the first to examine the effects of threatening – but not physically painful – stimuli on mice with earlier injuries.  

“We took what might be described as a psychological angle by using predator odour as a danger cue,” says Martin, whose research uses animal models to investigate the role of cognitive and social factors on the experience of pain.  

While the nervous system’s ability to detect potential danger and/or pain is vital for survival, that capacity can go into overdrive, he says.

“Sometimes that protective system stays switched on – leaving us overly sensitive to stress or pain even when the threat is long gone,” says Martin.

The research team uncovered the biological pathways that trigger such hypervigilance. They found that the stress hormone corticosterone in mice, which is similar to cortisol in humans, interacts with a protein called TRPA1 to increase sensitivity to possible threats.  

In the injured mice, which had abnormally high corticosterone levels in the presence of a predator odour, this produced exaggerated fear and pain responses.  

The researchers then blocked production of the stress hormone and discovered they could prevent increased fear and long-lasting pain responses after the threat. Blocking the TRPA1 protein alone only prevented the increased fear, the study found.  

“These findings suggest that fear and pain responses might have distinct underlying biological mechanisms,” says Baumbach.

The research could have significant implications for treatment, says Martin.

“There’s a lot of connection between pain persistence and fear in people,” says Martin. “If we can start to develop models where we dissociate the two, we might have different intervention points for prevention and treatment.”

The study findings could also increase scientists’ understanding of chronic pain that can’t be traced to an event or injury.

“Until now, there haven’t been animal models available where a non-painful event gives rise to pain-related behaviour,” says Martin.  

Going forward, the researchers are exploring the precise brain and central nervous system circuits that control the magnified fear and pain behaviour.  

“Our aim is to uncover the ways in which prior pain experiences shape the brain to produce enhanced fear and long-lasting pain,” says Martin. “This will allow us to come up with more targeted hypotheses and approaches to help leverage the new knowledge for clinical applications.”