Over the past 15 years, neuroscientists have pieced together one particular biological circuit that they think is involved in some chronic pain conditions. But work on this mechanism left out some important subjects: females.
A new study highlights the risk of ignoring sex in biomedical research. The researchers report that female mice don’t develop a certain type of pain through the same mechanism that males do. This profound sex difference, the authors say, shows the likelihood of finding an incomplete picture of biological phenomena when running experiments solely on male animals. If a similar difference exists in human beings, it could have significant implications for the development of new pain therapies.
“The study is another in a growing number of examples showing how sex influences biology from cells to selves,” says Janine A. Clayton, the National Institutes of Health associate director for research on women’s health. “Studies like this show that it’s vital to study both sexes.”
Clayton’s office and others at NIH have been working on new policies to encourage scientists to consider sex differences in biomedical research. Last month, NIH announced plans to add instructions to grant applications that would ask scientists to account for sex as a variable in their proposed research.
In the mouse pain study, Jeffrey S. Mogil of McGill University, in Montreal; Michael W. Salter of the University of Toronto; and coworkers looked at a well-studied circuit involving cells in the spinal cord called microglia. Inflammation or nerve damage causes these cells to send signals to nearby sensory neurons, switching those cells from inhibitors to amplifiers of pain.
Most of the work establishing this mechanism was performed using male mice. Researchers often worry that the hormonal changes in the female estrous cycle complicate animal studies by adding in another set of variables.
However, in a previous study, Mogil, Salter, and other team members found that a certain receptor on microglia helped trigger pain hypersensitivity in male mice but not in females. So they wondered if the difference was bigger than just one protein.
To find out, the researchers used genetic engineering and small molecules to inhibit each step of the microglia-neuron pathway in male and female mice suffering from nerve injuries. Blocking individual parts of this circuit decreased pain sensitivity in males but not in females, suggesting that the circuitry was not active in female mice. In fact, when the researchers depleted microglia from the spinal cords of females, the animals remained hypersensitive to pain.
Through further experiments, the team tentatively identified T cells as the immune cells involved in enhancing female sensitivity to pain (Nat. Neurosci. 2015, DOI: 10.1038/nn.4053).
Salter was surprised that the two sexes use different cell types for the same process. “Every time I talk about this, I look at the audience, and I can tell they simply don’t believe it,” he says. “And I tell them, ‘I didn’t believe it either at first.’ ”
Mogil and Salter think it’s possible that a similar sex difference exists in people. If so, it would mean drug developers would need to take sex into account when working on new pain therapies.