Pain may take different pathways in men and women

Men and women experience pain differently, and until now, scientists didn’t know why. New research says it may be in part due to differences in male and female nerve cells.

Pain-sensing nerve cells from male and female animal tissues responded differently to the same sensitizing substances, researchers report June 3 in Brain. The results suggest that at the cellular level, pain is produced differently between the sexes.

The results might allow researchers “to come up with drugs that would be specific to treat female patients or male patients,” says Katherine Martucci, a neuroscientist who studies chronic pain at Duke University School of Medicine and was not involved in the study. “There’s no debate about it. They’re seeing these differences in the cells.”

Some types of chronic and acute pain appear more often in one sex, but it’s unclear why. For instance, about 50 million adults in the United States suffer from chronic pain conditions (SN: 5/22/23). About 50 percent of chronic pain conditions (such as rheumatoid arthritis and migraines) are more prevalent in women, while 20 percent (such as gout) are more prevalent in men. Similar disparities exist for acute conditions.

Such differences prompted pain researcher Frank Porreca of the University of Arizona Health Sciences in Tucson and colleagues to study nerve cells called nociceptors, which can act like alarms for the body. The cells’ pain sensors, found in skin, organs and elsewhere in the body, can detect potentially dangerous stimuli and send signals to the brain, which then interprets the information as pain. In some cases, the nerve cells can become more sensitive to outside stimulation, registering even gentle sensations — like a shirt rubbing sunburned skin — as pain.

Using tissue from mice, monkeys and humans, the researchers studied the effects of two substances that can sensitize nerve cells to pain: a hormone called prolactin and a neurotransmitter dubbed orexin B. When the nerve cells detect these substances, they become more sensitive to stimuli, lowering the threshold at which cells send electrical signals to the brain to signal that something is wrong. Across all three species, exposure to prolactin made nerve cells from females more active compared with those from males. Orexin B had the opposite effect, boosting the activity of nerve cells from males.

The data indicate that there are differences between men and women even at the first step in the pain pathway, says study coauthor Harrison Stratton, a neuroscientist at the University of Pittsburgh.

If the driving forces that produce pain differ between sexes, then pain medicines can be tailored for males or females, Porreca says. This could mean blocking sensitivity to prolactin in females and to orexin B in males. The two substances have already been widely studied for their involvement in other body processes such as lactation and sleep. Some orexin blockers approved by the U.S. Food and Drug Administration to treat insomnia could be repurposed for pain. And Porreca and colleagues previously discovered a prolactin-blocking antibody, which could hold promise for treating a variety of conditions from female pain to infertility.

Typically, discoveries about pain in mice do not translate cleanly to humans. But since the particular pain pathway tested in the study seems to operate similarly across mice, monkeys and humans, future drugs targeting prolactin and orexin B could turn out to be a good way to manage pain following further research and testing, Martucci says. “It’s giving us a really good vision for how to move forward.”

But Richard Miller, a pharmacologist at Northwestern University Feinberg School of Medicine in Chicago, notes that though the study finds differences between the sexes, pain is often caused by a confluence of many other potential factors. That means there may be many other substances that would have shown similar results, he says, calling into question whether prolactin and orexin B are uniquely important targets.