Another difference between the sexes

BIRMINGHAM, Ala.—The U.S. National Institutes of Health recently unveiled a new policy, similar to one already in force in Canada, to require the use of female animals and cell lines in preclinical research. And the impact of this decision is already being felt.

“The current findings from this paper are an excellent example of the wisdom of this policy,” said Robert Sorge, Ph.D., whose team at the University of Alabama at Birmingham published research results today in Nature Neuroscience online that challenge the common belief that males and females process pain in the same way. “Introducing female animals into research will ensure that we can identify problems and conditions that may be mechanistically differently in each sex.”

The majority of existing research shows that men and women have different sensitivity to pain, with women being more sensitive to pain overall, but the assumption has always been that a common pain circuit exists in both sexes that is altered by circulating hormones such as estrogen.

Sorge and colleagues from three laboratories in the United States and Canada found that this assumption may be false, and that males and females may use very different biological systems to process pain. The key sex difference appears to be in the immune system, and under control of the male hormone testosterone.

“Realizing that females likely process pain differently than males will allow us to focus on creating alternate pain therapies for each sex,” said Sorge, an assistant professor in the department of psychology in UAB’s College of Arts and Sciences. “Females could respond better to a treatment that is different from what is prescribed for males—that’s something we as researchers were not looking at before, and this study has helped us uncover that need.”

For years, researchers who study the brain did not think the immune system had much to do with brain functions such as producing pain, but now it is known that the immune system does a lot more than just fight off infection, and actually works in conjunction with the nervous system.

For example, many experiments have shown that one immune cell, called microglia, is critical for pain processing. When activated by injury like inflammation or nerve damage, microglia sound the alarm by changing their shape and releasing chemicals. These chemicals communicate with nearby neurons in the spinal cord to turn up the volume knob of pain.

The findings from Sorge and colleagues show that this process only occurs naturally in male mice. Interfering with the function of microglia in a variety of ways blocks pain in male mice, but has no affect whatsoever in female mice. T cells, a completely different type of immune cell, appear to be responsible for releasing the same chemicals and sending the same signal in female mice. The study also found that females are able to use the male system in instances when the female system is not available or when high levels of testosterone are present.

“Given that women greatly outnumber men as sufferers of chronic pain, one might wonder why it is that this sex difference was not noted until now,” Sorge said. “The reason is that, as in most pain research, the overwhelming majority of the studies of microglia and pain were performed only on male rats and mice.”

The paper detailing the research, “Different immune cells mediate mechanical pain hypersensitivity in male and female mice,” was published today in Nature Neuroscience online.

The work was supported by grants from the Canadian Institutes for Health Research, Louise and Alan Edwards Foundation, and the U.S. National Institutes of Health.

Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is an internationally renowned research university and academic medical center and the state of Alabama’s largest employer, with some 23,000 employees and an economic impact exceeding $5 billion annually on the state. The five pillars of UAB’s mission are: the education of students, who are exposed to multidisciplinary learning and a new world of diversity; research, the creation of new knowledge; patient care, the outcome of ‘bench-to-bedside’ translational knowledge; service to the community at home and around the globe, from free clinics in local neighborhoods to the transformational experience of the arts; and the economic development of Birmingham and Alabama.