Memory of pain enhances pain responses in males, not females: Study

Interestingly, females do not react in this way and appear not to recall the experience.

“If pain is experienced in a particular environment and it is revisited, this heightens the pain response in males,” says Martin, who is also the Tier II Canada Research Chair in Translational Pain Research. “This is an important finding because increasing evidence suggests that chronic pain is a problem to the extent that you remember it, and this study is the first time such remembered pain has been shown using a translational – both rodent and human subject – approach. If remembered pain is a driving force for chronic pain and we understand how pain is remembered, we may be able help some sufferers by treating the mechanisms behind the memories directly.”

The study, which appears in the Jan. 10 issue of Current Biology, highlights the difference between sexes in how pain is remembered, which may shed some light on the maxim that if men had to give birth, the world wouldn’t have many families with multiple children.

In conducting their research, Martin and his colleagues tested pain memory in men and in male mice compared to appropriate control groups. Both men and women were brought into a room where heat sensors were first applied to their skin. Next, they were taken into a room where their arm was banded with a blood pressure cuff, that was inflated tightly for 20 minutes; each subject was asked to raise his or her arm, further tightening the cuff to increase the sensation. The following day, each subject returned and sensors were once again placed on the arm. When they were taken into the same room as in the previous test, the men exhibited a much higher level of pain than the women, even though no cuff was applied.

“We believe that the men were anticipating the cuff and, for the men, the anticipation caused greater pain sensitivity,” Martin says.

With mice, each mouse received a diluted injection of vinegar to cause mild stomach pain before they were removed to an environment where a light was shone on their paw, to produce a heat pain response. Twenty-four hours later, the mice were either placed in the same cage or a differently-shaped cage. Male, but not female mice returning to the same environment exhibited a heightened heat pain response; while mice placed in a neutral environment did not.

“The male mice and men who returned to similar environments showed a greater stress response and pain sensitivity; we believe they were anticipating pain,” Martin says.

The researchers hypothesized that the pain response might be related to the body’s sex hormones. They compared male mice compared to castrated mice during the experiment. The castrated males, in this case, did not show greater pain responses, while testosterone administration to females caused greater sensitivity, allowing Martin and his fellow researchers to determine that testosterone is involved in pain memory.

“There are sex differences in how we remember pain,” Martin says. “These implicit memories change our physiology.”

Given that pain appeared to recur due to memories of previous pain, Martin and his colleagues interfered with memory by injecting the brains of male mice with a peptide known to erase memory. When they ran the pain memory experiment, these mice didn’t show signs of remembered pain.

“We are following up by trying to determine the areas of the brain that might be active during remembered pain so we can understand the mechanisms and target them,” Martin says. Understanding the physiological roots of remembered pain may make it possible to develop treatments for persistent pain.