Recently, an article by Clayton and Collins (2014) shook up the preclinical (and clinical) research environment. Although the article did not present new experimental findings, it was polarizing in that it suggested that the National Institutes of Health would require researchers to include sex as a variable in their experiments. In contrast to the National Institutes of Health Revitalization Act of 1993, which requires female patients to be included in clinical studies, very little had been done to promote this change in preclinical research, although it was a subject of regular commentary (Mogil and Chanda, 2005; Mogil and Bailey, 2010; Zucker and Beery, 2010). Sex differences have been recognized for decades in a number of fields of research. However, although researchers have acknowledged their existence, few have addressed these differences in their work. A seminal article by Beery and Zucker (2011) examined the articles published in 2009 based on humans or animals in different fields and to determine whether they included one sex, both sexes, or unspecified sex. Animal studies were overwhelmingly performed with male animals (or unspecified), whereas human studies tended to examine both sexes. Perhaps the most compelling finding was that, across most disciplines, sex was not analyzed in the results, and the most surprising aspect was that less than 10% of immunology articles included an analysis of sex.
This Review focuses on the biological basis for sex differences in pain, with special attention to immune system differences between male and female subjects that may underlie the observed differences. Once again, sex differences have been identified in clinical pain populations (Berkley, 1997), the disparity in the use of male and female animals in preclinical research has been thoroughly noted, and a “call to arms” has been raised (Mogil and Bailey, 2010; Mogil, 2012). This Review does not seek to reiterate the exceptional surveys of the extant literature at a clinical level but rather seeks to highlight the fact that the differences exist and that they may be underpinned by observed differences in the functioning of the immune system.