The study of pain is essential to biomedical research for many reasons. Signs and reports of pain can inform diagnoses and prognoses by conveying the severity of symptoms or the efficacy of treatment. Untreated pain can also have a deleterious effect on a patient's wellbeing and quality of life. Finally, in biological research it is the ethical responsibility of investigators to reduce and minimize pain in their subjects whenever possible. It is important, therefore, to understand the physiology of pain and the mechanisms by which treatments can relieve pain in humans and animals.

Previous research on the pathophysiology of pain has yielded one prevailing model of chronic pain, wherein glial cells are thought to initiate and maintain chronic pain in response to peripheral injuries. Recent findings indicate that this explanation is only half-true: in women, chronic pain is instead mediated by T cells (Nat. Neurosci. doi:10.1038/nn.4053; published online 29 June 2015).

“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 Jeffrey Mogil of McGill University (Montreal, Canada), who led the study alongside colleagues from the US and Canada.

Mogil's team discovered this difference when they used the spared nerve injury technique to model persistent neuropathic pain in both male and female mice. All mice showed allodynia, or mechanical hypersensitivity, after the injury, but only male mice lost their allodynia when injected with glial inhibitors. Females continued to show allodynia after receiving the same injection and after receiving an injection of saporin toxin that depleted their microglia.

The researchers then recreated the chronic pain model using strains of mice that are deficient in T cells and found that glial inhibitors successfully relieved allodynia in both males and females. Taken together, these findings suggest that the female pain response induces allodynia preferentially through T cells, as seen in the wild-type mice, but functions through glial cells only when T cells are deficient.

The presence of a sexual dimorphism at the physiological level is not surprising in and of itself. Rather, the authors note, it is surprising that this difference has remained unnoticed for so long. These findings advance our understanding of pain in mice and potentially in humans, but moreover they underscore the importance of reconsidering accepted conventions and assumptions of common research models.