The Origin of Pain Differs Wildly Between the Sexes

Of the approximately 100 million Americans that experience chronic pain, 70 percent are women. However, it wasn’t until 2014 that the National Institutes of Health demanded that preclinical experiments had to include both male and female animal models: Before then, 80 percent of pain studies were conducted on only male mice. The opening of those gates has confirmed long-held suspicion: On a cellular level, pain differs between men and women.

Research published Tuesday in the Journal of Neuroscience is evidence that the mechanisms that drive pain are very separate for the two genders. In a study on male and female mice, researchers from the University of Texas at Dallas show that pain in the different sexes comes down to distinct pain receptors, and it’s very likely that human pain has similarly sex-specific origins. The authors acknowledge that the science community’s ignorance of the sex disparity has been a decidedly un-woke oversight.

“We’ve been overlooking a key variable for a long time, and I’m as guilty as everyone else,” said co-author Dr. Ted Price in a statement. “Professionally, we saw no reason to do it until 2014. But we’re discovering that the NIH decision was the right thing. Everyone I know doing these studies is finding new and interesting mechanisms that we’ve simply overlooked.”

In the new study, Price and his team focused on a newly discovered pain mechanism that works via D5 dopamine receptors, one of several receptors in the brain that bind the neurotransmitter dopamine.

When the researchers genetically engineered all of the mice to have no D5 receptors, it was only the male mice that showed significantly reduced pain responses. Pain in female mice, they write, traveled via D1 receptors, which “could be explained by sexual dimorphisms in receptor expression levels.”

This discovery, says Price, is a “very clear indication that there are extraordinarily strong mechanistic sex differences in how pain becomes chronic.” It’s an important realization that he says wouldn’t have happened unless they were forced to examine both male and female mice.

Identifying sex-specific pain relief targets opens the door for male and female-specific drugs for chronic pain. Since removing D5 in male mice reduced pain, then perhaps creating a D5 antagonist drug — one that blocks the receptor from binding pain-causing agents — could alleviate chronic pain in male mice. In theory, the same could be said for D1 receptors in female mice and in the parallel pain receptors in humans, if they ever see the same results in human tissues.

Price hopes that his research will encourage doctors to consider sexual dimorphism when treating pain and, in turn, create solutions that help people on a wider level.

“Those running clinical trials for the last five years have been frustrated because the preclinical results don’t come through in the clinical results,” he says. “The cause of this problem, potentially, is that up until recently, many of the preclinical investigators were just using males. Then, in the clinical trials, human participants are primarily female, because more women suffer from chronic pain in men.”

This gender gap, unfortunately, widens far beyond women with chronic pain failing to get the medication they need. Women are twice as likely to develop multiple sclerosis, two to three times more likely to develop rheumatoid arthritis, and four times more likely to have chronic fatigue syndrome than men, noted the New York Times in 2013, yet historically they have been less responsive to the drugs developed to treat these ailments as well as to standard drugs like anesthesia and ibuprofen. The upsetting implication is that drugs have been designed under the assumption that male pain is the same as everyone’s pain, but as scientists are finally discovering, the bodies of men and women are different — and need to be treated as such.

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