Male and female mice transmit pain signals differently, surprising research has found. Some methods of pain control give relief to male rodents, but not to females. If the findings are replicated in humans, they could transform how we tackle hard-to-treat pain.

“Research has demonstrated that men and women have different sensitivity to pain and that more women suffer from chronic pain than men, but the assumption has always been that the wiring of how pain is processed is the same in both sexes,” said Professor Jeffrey Mogil of McGill University, Canada.

Mogil is a senior author of a paper in Nature Neuroscience investigating the theory that microglia cells carry pain signals from sites of damage to the brain. Microglia are known to clean up harmful proteins within the brain, such as those that cause Alzheimer's Disease, but they also exist in the spinal cord, which suggests that they have other roles.

In the process, however, Mogil and his colleagues found something completely unexpected. When they interfered with microglia function, the male mice were freed from pain, but the females continued to suffer.

Clearly, the female mice must have a matching transmission method. The authors found evidence that T cells, the white blood cells widespread in the immune system, play the equivalent role in females, but they admit that they don't yet understand how this occurs.

“Understanding the pathways of pain and sex differences is absolutely essential as we design the next generation of more sophisticated, targeted pain medications,” said senior coauthor Professor Michael Salter of the University of Toronto.

Pain transmission is complex, with multiple pathways transmitting different sorts of pain, which is why different sorts of painkillers are effective against different types of injury or illness. Earlier work by Mogil showed that emotional states can change the efficiency of painkillers, and that the sex of the researcher can affect rats' pain response.

Not all medical discoveries in rodents are applicable to humans, but Salter says that mice and humans have “very similar nervous systems.” Pain is such a deep evolutionary function that it tends to be well conserved across mammalian species, making the sexual differences even more intriguing.

While the discovery raises exciting opportunities for finding methods to reduce suffering by matching the pain relief to the patient, Mogil says that it also has implications for the way we do research.

“The realization that the biological basis for pain between men and women could be so fundamentally different raises important research and ethical questions if we want to reduce suffering."

The finding occurred in part because Canada has policies pushing researchers to use both male and female animals and cell lines. “For the past 15 years scientists have thought that microglia controlled the volume knob on pain, but this conclusion was based on research using almost exclusively male mice,” said Mogil. “This finding is a perfect example of why this policy, and very carefully designed research, is essential if the benefits of basic science are to serve everyone.”

The US National Institutes of Health last year announced an intention to address “the over-reliance on male animals and cells” in clinical studies.