“Pain Memories” Exhibited Primarily in Males

Sex differences continue to play a huge role in the pain experience.

With Tina Doshi, MD, MHS

For decades, researchers have studied the distinct ways in which men and women experience and respond to pain, including hypersensitivity or increased sensitivity to the feeling of pain. A new study conducted on both mice and humans has shown that males, in particular, seem to have what’s called “context-dependent” pain hypersensitivity. This means that when they are placed in an environment that previously led to or caused them pain, they are hesitant to re-enter that space. This ability to associate specific feelings in connection with specific locations may be linked to stress—and the researchers believe testosterone may be a key factor.

The study was led by Jeffrey S. Mogil, PhD, a psychology professor at the Alan Edwards Centre for Research on Pain at McGill University in Montreal, and a group of researchers at the University of Toronto. “Upon further examination of potential hormonal influences,” they wrote in their published study, “we found that endocrine stress response and testosterone played a role.”

According to Tina Doshi, MD, MHS, an assistant professor of pain medicine at Johns Hopkins University School of Medicine in Baltimore, “This fascinating work provides new insights into the mechanisms of sexual dimorphism (that is, different characteristics between two sexes of the same species, beyond sexual organs) in pain processing and raises intriguing questions about how and why men and women seem to experience pain differently.” Dr. Doshi is also a member of the PPM Editorial Board.

“Pain memories” may somehow be encoded in the spinal cord, researchers speculate. (Source: 123RF)

Blocking Hypersensitivity

To test their theory, the researchers placed mice in a cylinder and examined how quickly the mice pulled away their paws when exposed to heat. The mice were then injected with acetic acid, a substance that causes abdominal cramps and writhing for up to 30 minutes before returning the mice to their cages. The next day, the mice were placed either back in their cylinder, or in a separate cubicle, and again tested for pain sensitivity to heat. Male mice tested in the same context (cylinder), but not a different context (separate cubicle), were more sensitive to pain on Day 2.

On both days of studying, researchers used a drug called metyrapone to block the hypothalamic-pituitary-adrenal (HPA) axis, an area of the central nervous system (CNS) known for its brain-body stress communication system, from making corticosterone (a hormone developed in the adrenal glands). The substance prevented hypersensitivity in male mice without affecting female pain behaviors; male mice in the same environment had higher corticosterone levels than mice that did not develop hypersensitivity.

Additionally, researchers separately blocked pain hypersensitivity with an injection of zeta inhibitory peptide (ZIP), a chemical that inhibits the molecules atypical protein kinase C (aPKC), which are key in memory formation. These injections prevented hypersensitivity when injected into the mice’s spinal cord or into the cerebrospinal fluid, a clear, watery fluid that coats the area around the brain and spinal cord.

The human study, by comparison, involved 41 male and 38 female subjects who self-rated their pain level when a heat probe was placed on their forearm. Afterward, a 20-minute session with a heavily pumped blood pressure cuff was applied to the same arm. The following day, further heat probe testing was conducted; half the subjects came back to the same room with the same supervisor, and the other half were retested in a different building by a different supervisor. Researchers then asked the participants to fill out a series of questionnaires to gauge their mood and stress levels on both days of testing.

Men, much like their mice counterparts, retested in the same context environment reported significantly higher stress levels than the day before; a key phenomenon observed by the researchers. “A reasonable interpretation is that males more effectively recalled (or were more emotionally affected by recalling) the stress-inducing properties of the context on Day 2 of testing,” they wrote.

Pain “Memory”

Researchers concluded that testosterone may explain this difference, since further examinations on castration (the removal of male reproductive glands which reduces the production of testosterone) abolished the pain hypersensitivity in male mice that had already developed it. In contrast, an ovariectomy, the surgical removal of one or both of the ovaries, had no effect on pain in female mice.

The pain hypersensitivity shown in males on the second day of testing could be the manifestation of a “pain memory,” they further theorized. The researchers note, however, that this type of “pain memory” is not necessarily a “conscious” one.

In an accompanying editorial published in the same issue as the study, third-party experts speculated that ZIP might have caused these changes in how the brain’s neurons communicate in mice. They also suggested that the “pain memory” may somehow be encoded in the spinal cord, with brain activity being the underlying driver of the emotional component of the memory.

What Does This Mean for Me?

“Regardless of the possible underlying explanation, it is clear that the experience of pain is highly individual,” Dr. Doshi says. “In this series of studies alone, the researchers have shown that context, memory, stress, and sex can all influence pain processing in complicated, interrelated, and sometimes unpredictable ways. [These factors] are biological variables that inform the overall clinical picture of chronic pain, and they provide a guide to tailoring treatment approaches accordingly.”

Dr. Doshi notes how these findings should not be oversimplified to say that male and female patients should be treated differently in pain management, or that “blunting stress responses or altering memory would be good (or even desirable) ways to prevent clinical pain.”

“People with bad memories still have chronic pain, and past painful experiences are not automatic harbingers of future pain sensitivity,” Dr. Doshi explains.

Dr. Mogil and his team believe future studies should look at the role cortisol—the body’s stress hormone—may play in males as well as there could be links to pain response.

To read more on sex differences in the pain experience, particularly as it pertains to women’s pain, click here.

Updated on: 06/20/19
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