For a long time, scientists did not often carefully consider sex as a variable in their research, and often worked with only male or only female animals depending on the ease of housing and handling these animals. In 2016, the NIH began requiring grant applications to justify the choice of sex of experimental animals, as part of a growing movement to consider sex as a biologically relevant variable. One surprising discovery? Men and women do not experience pain in the same way – and hormones may be playing a big role.

Pain is important for life. It allows individuals to withdraw from situations – like a sharp object or a hot stove – that might otherwise be toxic or damaging. For the most part, pain should be transient, lasting for only the length of the noxious stimulus. However, in ~20% of people, this pain response lasts too long. Interestingly, the majority of people who experience chronic pain are women.

A team led by Robert Sorge at McGill University in Montreal, Canada has deciphered some of the biology behind these sex differences in pain. Sorge and his team knew that injecting a bacterial molecule called lipopolysaccharide (LPS) into the spines of mice led them to be exquisitely sensitive to pain; even the slightest touch would cause the mice to yank their paws away. Before long, the researchers realized that this pain hypersensitivity was unique to male mice. In female mice, nothing happened.

Why the difference? Increasingly, scientists are realizing that there are multiple different pathways of inflammation – with different sets of cells and molecules – that all culminate in the experience that we call pain. Sex seems to influence which pathway is chosen. Several studies have suggested that male mice may rely more on pain pathways that include microglia, a type of immune cell that resides in the nervous system, while female mice may rely more on a different kind of immune cell, called the T cell. The male sex hormone, testosterone, seems to play a big role. When researchers castrated male mice (effectively lowering the testosterone level), the mice no longer displayed pain hypersensitivity after the LPS injection. In contrast, when castrated male mice were given testosterone, or when testosterone was given to female mice, the pain pathway switched back to the male microglia-dependent pathway. Further studies will be necessary to determine why these pathways seem to be so strongly linked to sex and the production of sex hormones.

This research has a host of implications, both for basic research and for drug development. Pre-clinical pain research has often used exclusively female rodents, because they are less aggressive and easier to handle. On the other hand, early clinical trials testing the safety of new therapeutics often exclude pre-menopausal women, as they could become pregnant. However, it is increasingly obvious that sex is a powerful driver of the way we experience pain. Understanding the differences between sexes in pain research may lead to the development of sex-specific pain drugs.

Original Review Article:

Managing Correspondent: Radhika Agarwal

Image Credit: Pixabay

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