What’s the difference between pain and stress? Pain is a physical response to harmful stimuli, and stress is a physical response to any threat. Pain causes stress, but stress does not require pain.

In an influential article in the journal, Chronic Stress, researchers from the Yale University School of Medicine explain the relationship between pain and stress. They examine the limbic brain under conditions of chronic pain, depression, and post-traumatic stress disorder (PTSD). They write:

The limbic brain — including hippocampus, amygdala, and ventromedial prefrontal cortex — plays a critical role in learning. These brain areas integrate incoming […] stress signals with internal state, and generate learning signals necessary for decision-making.

The authors make the intriguing statement that “chronic stress and chronic pain share a common behavioral model of failure to extinguish negative memories.” It is this failure to extinguish negative memories that we are going to examine in today’s post, beginning with the review in Chronic Stress.

“Pain and stress are both adaptive in protecting the organism,” the researchers begin. “However, if either of the two processes becomes chronic, it can lead to long-term ‘maladaptive’ changes in physiology and consequently behavior, resulting in suffering and compromised well-being.”

As important as pain and stress are to survival, the ability to extinguish fear is also important. “Extinction of the fear association, or the unlearning of the fear, occurs when the conditioned stimulus is presented multiple times without the unconditioned stimulus.” Fear is extinguished when behavior is disconnected from pain.

However, “PTSD and chronic pain can be considered conditions where the brain fails to extinguish the negative memory.” The hippocampus, the amygdala, and the pre-frontal cortex “each play a critical role in fear learning and extinction.”

The hippocampus is active during acute stress but rarely during acute pain. It contributes to fear extinction by “down-regulating” the response to stress. “Chronic pain and stress-related psychiatric disorders have been associated with shrinkage of the hippocampal volume,” write the researchers. The effect is so pronounced that hippocampus volume accurately predicts the recurrence of back pain after surgery.

This research might explain the neurological benefits of frightening amusement park rides, which cause increased neurogenesis due to the stress response followed by enhanced memory extinction capabilities. Scary movies biologically strengthen our abilities to put bad memories to rest.

The amygdala responds to both stress and pain and is hyperactive in chronic-stress-related conditions such as PTSD. “Chronic stress and chronic pain are both associated with dendritic growth in the amygdala,” and “humans suffering from depression, PTSD, or chronic pain were found to have smaller amygdala.” Again, this effect is so pronounced that total hip replacement surgery leads to an increase in amygdala volume upon remission of hip pain.

The prefrontal cortex (PFC) is also involved in the management of stress and pain. However, the two conditions appear to take different paths. Acute stress in healthy people increases PFC volume, but PFC volume shrinks with chronic pain, PTSD, and depression.

Researchers at the Max Planck Institute of Psychiatry in Munich, Germany, conducted research on mice to determine the mechanism for the acquisition, storage, and extinction of memories. Their findings:

[T]he endogenous cannabinoid system has a central function in extinction of aversive memories.

The researchers raised mice deficient in cannabinoid receptor 1 (CB1) and found this resulted in a “strongly impaired” ability to extinguish both short-term and long-term memories of fear. Similarly, they treated “wild-type mice” with a CB1 antagonist and found that the presence of CB1 is essential for memory extinction. The researchers conclude:

We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.

An interesting study out of Rome found that forgetting is “an active process […] suggesting that the brain actively works to suppress retrieval of unwanted memories.” The failure to suppress unwanted memories is “a common feature of many mental health disorders.” Neurobiological studies show there is a whole-brain mechanism in force to “actively erase memories” involving “adult neurogenesis remodeling of hippocampal circuits.”

Their research shows that “alterations in glutamatergic and GABAergic transmissions” are a common feature of numerous disorders, including schizophrenia, depression, PTSD, and obsessive-compulsive disorder. That raises the possibility that GLP-1 drugs such as Ozempic and Wegovy are effective, in part, because they elevate the ability to forget painful memories.

We will soon continue this fascinating look at the ability to extinguish memories and how that can be manipulated to improve mental health.

Written by Steve O’Keefe. First published August 10, 2026.

Sources:

“Chronic Pain and Chronic Stress: Two Sides of the Same Coin?,” Chronic Stress, June 8, 2017.

“The endogenous cannabinoid system controls extinction of aversive memories,” Nature, August 1, 2002.

“Forgetting Unwanted Memories: Active Forgetting and Implications for the Development of Psychological Disorders,” Journal of Personalized Medicine, March 26, 2021.

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