Why men and women feel pain differently

We have different pathways for pain sensitivity

We feel pain when receptors in our skin, muscles, joints, or organs register a potentially dangerous sensation. For example, high fever or tissue damage. They send a signal along peripheral nerves to the spinal cord and then to the cerebral cortex, which interprets these signals as "painful!"

Although from the outside all pain looks the same, it cannot be assumed that the same processes are involved in its formation.

The pain is manifold. There is an urgent reaction to something hot or sharp, and there is chronic pain that does not go away even after the injury has healed. It manifests itself as hypersensitivity to stimuli that usually do not cause painful sensations.

This was the case with Sorge's mice. In 2009, he and Jeffrey Mogil, a behavioral neurologist, studied chronic pain caused by inflammation. They introduced into the spinal cord of mice a molecule of lipopolysaccharide, one of the components of bacterial cells.

The molecule has attracted the attention of microglia - immune cells of the nervous system. But inflammation occurred only in males - in females, microglia were not activated. It was because of this difference that the males were so sensitive to tingling with fine hairs, and the females did not seem to notice it.

Sorge and Mogil then injured the sciatic nerve in mice of both sexes. This has resulted in chronic pain, which usually occurs when the body's pain detection system is damaged or malfunctioning. Both males and females have become hypersensitive to touch. But the differences were still there.

Pain threshold for men and women: two paths to pain

In a previous experiment, it was found that in males, microglia play an important role in the perception of pain. And if they are blocked, the sensitivity to pain decreases. But this is not the case with females. As much as the researchers blocked their microglia, pain sensitivity remained high. It turned out that in their bodies another component of the immune system - T-lymphocytes - is behind the chronic pain.

Sorge tested this in females with similar nerve damage but T-lymphocyte deficiencies. They, too, became hypersensitive to the touch of fine hairs, but now microglia were included in the perception of pain. That is, the animals switched to the "male" type of pain sensitivity.

If the microglia activity was blocked in these females, the reaction disappeared - just like in the males. And when the scientists injected T-lymphocytes back into the females, they stopped using microglia - they switched back to the "female" type.

Perception is affected by testosterone

The question arises: what controls the switching between different pathways of pain sensitivity. Researchers have long attributed the difference in pain perception to estrogen. This hormone controls the formation of the uterus, ovaries and mammary glands, and also regulates the menstrual cycle. Estrogen can increase and decrease pain depending on the concentration in the body.

But testosterone has received little attention in the past.

Grave's work clearly indicates that it is testosterone that switches pain pathways. When he and Sorge castrated male mice (which lowered testosterone levels), the animals responded in the same way as females. And when scientists injected testosterone to females and castrated males, the path of pain sensitivity switched to the "male" version, that is, it involved microglia.

It is much more difficult to test how pain pathways work in humans, but the first information is emerging. Neuropharmacologist Ted Price found that in humans, the perception of pain is also influenced by immune cells. He and his colleagues studied the nerve tissue of cancer patients in whom the tumor has affected the spinal cord.

The nerves that had been excised from the men showed signs of inflammation caused by immune cells, macrophages. They are similar in function to microglia. In women, the nerve cells themselves and a short chain of amino acids that stimulate the growth of nerve tissue play a more important role in the perception of pain. This suggests that men and women may need different medications.

Medicines work differently on us

In 2018, Price discovered that the diabetes drug metformin reduced the number of microglia around sensory neurons in the spinal cord. And also the fact that it blocks hypersensitivity to pain only in male mice, but does not help females in any way.

Price put forward a hypothesis that explains such differences: metformin enters the nervous system with the help of a protein, which is expressed in large quantities in male cells. Increasing the dose of metformin does not help females because the drug cannot enter the nerve tissue.

However, increasing the dose helps in another case - with morphine.

“Both females and female rodents generally require a higher dose of morphine to relieve pain than males,” says Anne Murphy, a neuroscientist at Georgia State University in Atlanta. She is one of the few researchers who have long studied gender differences in pain perception.

In 2017, she and her colleagues discovered that microglia were also responsible for the different effects of morphine. Morphine dulls pain by blocking neurons in an area of the brain called the periaqueductal gray matter (WWS). But it can also activate microglia in this area, which neutralizes the analgesic effect. This is exactly what happens to female rats, because they have more active microglia in the WWS than males.

In Murphy's experiment, all rats were given morphine, and then they began to heat the surface under the hind legs of the animals. Since female rats have more microglia in the WWS, they had more inflammatory processes in this area.

As a result, their sensitivity to pain increased and they pulled back their paws faster than males who received the same dose of the substance. When the researchers eliminated the effect of morphine on microglia, males and females began to respond in the same way to pain stimulus.

And the difference in drug action isn't just in mice.

There is already at least one drug on the market that works differently for men and women. This is a migraine prevention remedy released in 2018. It includes antibodies to cocalcigenin, a protein that plays an important role in the development of seizures. It is known that women suffer from migraine more often - there are three times more of them than men with this disease.

Price conducted an experiment with cocalcigenin. He injected this substance into the dura mater of mice. In females, the squirrel caused symptoms similar to migraines: they wrinkled, and their faces became hypersensitive to touch. The males, on the other hand, did not develop symptoms.

This means that their migraines can be caused by other factors. Cocalcigenin blocking drugs are probably not as effective for men. But during clinical trials of the drug, this was not tested.

And this is a fairly common situation. Clinical trials of drugs usually involve men and women, but there are not enough of them to tell the difference. It is possible that some pain relievers that have failed trials could have been successful if tested given gender differences.

And this should be reflected in the production of painkillers

Pharmaceutical companies today offer the same medicines for everyone, but that could be changing. It is still quite difficult to create drugs specifically for one gender or another. In the early stages of clinical trials, safety is paramount, which is why companies are excluding women of reproductive age. As a result, drugs are most often tested in men and women after menopause.

But even if drugs are developed separately for the male and female pathways of pain sensitivity, this may not be enough. Throughout life, people may need different pain relievers, depending on fluctuations in hormonal levels. In addition, a person's gender does not always fit neatly into the category of male or female. It is determined by a combination of factors: genetics, anatomical development, hormone levels.

Each of these factors can affect which pain reliever is right for a person.

So far, very little is known about the mechanisms of pain in humans that do not fit into the binary gender system. In one study, scientists in Italy surveyed transgender participants undergoing hormone therapy. 11 out of 47 people who made the transition from male to female reported the appearance of pain symptoms. Six of the 26 female-to-male transitions reported that their pain sensation was reduced after taking testosterone.

Now scientists have insufficient results, and most of the conclusions are based on research in rodents. However, they suggest that the medicines of the future will take into account the individual characteristics of consumers. Mogil believes that the pathways of pain sensitivity, and hence the choice of pain reliever in the future, depend on the level of hormones. In people with testosterone levels above a certain threshold, the "male" pathway of pain sensitivity is activated. And for those whose level of this hormone is below the border, it is "female".