EXPRESS: Impact of Estrous Cycle, Gonadectomy (Ovariectomy or Castration), and Selective G-Protein Estrogen Receptor Agonism on Inflammatory Pain in Wild-Type Mice

Inflammatory pain is a key component of acute traumatic pain and chronic rheumatic disease, which significantly reduces the quality of life of those who suffer from it and is often refractory to treatment. One contributor to the failure of current treatments is that the majority of pain testing has historically been performed in male subjects while the majority of pain patients are women. To better manage inflammatory pain, first the baseline sex differences in its experience must be assessed. Therefore, we evaluated C57BL/6J male and female mice for baseline sex differences in the formalin model of inflammatory pain, further investigating the observed significant sex differences through both assessing female mice at each phase of the estrous cycle and through examining the effects of gonadectomy (ovariectomy or castration) within the formalin model of inflammatory pain. Female mice in the metestrus or diestrus phase had decreased inflammatory pain relative to both male mice and female mice in the proestrus or estrus phase. Ovariectomy resulted in decreased pain, which was restored through treatment with estradiol (E2). Castration similarly reduced pain in male mice. Injection of the G-protein coupled estrogen receptor (GPER) agonist G1 resulted in significant antinociception in both female and male mice, in both mice that had received sham surgery or gonadectomy. These results establish baseline sex differences in the formalin model of inflammatory pain and support the need for further investigation into the interaction between estrogen, its receptors, and testosterone in the regulation of nociception.