Background & Aims

Chronic posttraumatic musculoskeletal pain (CPMP) following traumatic stress exposure (TSE) is a major public health problem. The incidence of CPMP after TSE is much higher in women than men,1 and preventive interventions that reduce this sex disparity are urgently needed. Estrogen has been shown to have analgesic and anti-inflammatory effects in several animal models and human pain conditions. We have shown that exogenous peritraumatic administration of 17?-estradiol (E2) in TSE-exposed female rats prevents CPMP-like behavior and found in 4 longitudinal observational studies that increased peritraumatic levels predict better CPMP outcomes.2 In the current study, we used human and animal data to evaluate molecular mediators contributing to the protective effects of peritraumatic E2 levels on CPMP-like behaviors/outcomes.

Methods

In humans, we utilized available nested microRNA, mRNA, cytokine (e.g. IL-6, IL-8, IL-10), hormone (e.g. E2, cortisol), and pain questionnaire data collected from women enrolled in the AURORA study3, a multi-site longitudinal study of TSE survivors (n>167). In animals, we used a well-validated model of TSE, the single prolonged stress model4, to induce enduring stress-induced hyperalgesia (n>6 animals per experiment). In TSE-exposed female ovariectomized rats treated with E2, we collected blood and dorsal root ganglia tissue and measured analytes in these tissues to match human studies.

Results

Human cohort-based analyses indicated that IL-10 partially mediated the relationship between peritraumatic E2 and CPMP. In animals, we similarly found that E2 influenced post-TSE IL-10 levels. In addition, mRNA and microRNA expression patterns in the blood of women TSE survivors were influenced by E2. These RNA-based changes were enriched in biological networks such as “neurological disease/psychological disorders” (Ingenuity pathway analysis, Qiagen). Specific microRNA and mRNA transcripts, e.g. miR-374b-5p also showed E2 responsive changes in dorsal root ganglia neurons. We are currently expanding the sample sizes of our human and animal biological data and will report updated results based on those larger cohorts at the meeting.

Conclusions

Protective effects of peritraumatic E2 in women are at least partially mediated by molecular changes observed in the blood and dorsal root ganglia tissue in humans and rats following TSE. Further studies are needed to fully understand molecular mechanisms driving the relationship between peritraumatic E2 levels and CPMP development and persistence in women.

References

.Beaudoin FL, Kessler RC, Hwang I, et al. Pain after a motor vehicle crash: The role of socio-demographics, crash characteristics and peri-traumatic stress symptoms. Eur J Pain 2021;25(5):1119-1136. (In eng). DOI: 10.1002/ejp.1733.
2.Linnstaedt SD, Mauck MC, Son EY, et al. Peritraumatic 17?-estradiol levels influence chronic posttraumatic pain outcomes. Pain 2021.
3.McLean SA, Ressler K, Koenen KC, et al. The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure. Molecular Psychiatry 2019. DOI: 10.1038/s41380-019-0581-3.
4.Yamamoto S, Morinobu S, Takei S, et al. Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depression and anxiety 2009;26(12):1110-1117.

Presenting Author

Jacqueline Mickelson

Poster Authors

Jacqueline Mickelson

BSc

University of North Carolina at Chapel Hill

Lead Author

E-mail

Simran Bhatia

Lead Author

Ying Zhao

Lead Author

Lauren McKibben

Lead Author

Alice Woolard

Lead Author

Liz Albertorio-Sáez

Lead Author

Samuel A. McLean

Lead Author

Sarah D. Linnstaedt

Lead Author

Topics

  • Models: Musculoskeletal