Starting with a seminal experiment performed in the laboratory of the late John C. Liebeskind at UCLA, we have uncovered evidence for the existence of male- and female-specific analgesia mechanisms in mice, and now humans. It appears that pain inhibition in male mice is dependent upon the activation within the brain of N-methyl-D-aspartate (NMDA) receptors; when they are blocked by NMDA receptor antagonists (like MK-801), pain inhibition is blocked in males but not females. We isolated a genomic region responsible for variability in pain inhibition in female but not male mice in 1997, and subsequent experiments revealed the responsible gene to be Mc1r, which encodes the melanocortin-1 receptor (MC1R). We believe that the MC1R is the female equivalent of NMDA. When MC1Rs are blocked or non-functional (as in spontaneous mutant e/e mice, shown in this picture at the top right), instead of pain inhibition being blocked, female mice are able to "switch" over to the male, NMDA-mediated system. This switching from one system to another may involve estrogen, and/or progesterone metabolites. Most importantly, in 2003 we showed that humans too appear to have separate, qualitatively distinct pain inhibition mechanisms, because human female "mutants" of the MC1R gene (more commonly known as "redheads") are more sensitive to a certain form of analgesia than are women of other genotypes (i.e., other hair colours), and all men.
The aforementioned discovery was made entirely by chance, and only occurred because we routinely test male and female mice in all experiments. We believe that basic pain researchers are loathe to include female subjects in their experiments because of a lingering belief that this sex displays more variability in their pain responses than do males. A recent paper tested this assumption by analyzing large archival datasets of tail-withdrawal and formalin test data compiled in both sexes and multiple strains. We find that it is male subjects that display higher (although not significantly so) variability. Given the practical advantages of using female mice (e.g., they're cheaper, and less aggressive to each other and to experimenters), and the ethical implications of not using them, we strongly encourage all pain researchers to consider performing their experiments on male and female subjects routinely.
