John Shannonhouse1
Yu Shin Kim1,2,3*
- 1Department of Oral & Maxillofacial Surgery, School of Dentistry, University of Texas Health Science Center, San Antonio, TX, United States
- 2Programs in Integrated Biomedical Sciences & Translational Sciences, University of Texas Health Science Center, San Antonio, TX, United States
- 3Center for Regenerative Sciences at University of Texas Health and Science Center – San Antonio, San Antonio, Texas, United States
Editorial on the Research Topic
Women in science: musculoskeletal pain
Sex differences have long been recognized as an important contributor to many aspects of biological phenomena and outcomes but have not been enough studied to the extent of their biological significance merits. Problems that disproportionately or exclusively affect women are widely recognized as under studied (1). Frontiers in Pain Research has devoted a research topic to studying musculoskeletal pain in women. Two areas of musculoskeletal pain that disproportionately affect women highlighted in this topic are lumbopelvic pain (LBPP) and intervertebral disc (IVD) degeneration (Table 1).
Table 1. Review of key points and references addressed by this editorial.
Pregnancy-related LBPP
Pregnancy-related lumbopelvic pain (LBPP) is a combination of pregnancy related lower back pain and pelvic girdle pain. Study of LBPP on large populations (>70,000) reliably find statistical correlations. However, smaller, mechanistic studies give varying degrees of inconsistent results (Daneau et al., 2). The efficacy of exercises to relieve pain and prevent chronification of pain, and which exercises are appropriate, are controversial (2, 3). Additionally, common problems including the difficulty of translatability of animal models, numerous changes to the body happening simultaneously during pregnancy, and differences and limited applicability of mixed or all-male pain studies contribute to a making a science-based approach to management of pregnancy-related LBPP difficult.
This review by Daneau et al. proposes an integrated approach of studying neuromechanical, physiological (including hormonal), second or later pregnancies, and clinical changes during all trimesters of pregnancy and interactions between these factors to disentangle the mixed evidence of mechanisms of pregnancy-related LBPP. They note one of the strongest predictors of LBPP is prior LBPP, suggesting (along with other evidence) that motor adaptations during pregnancy contribute to later LBPP. In addition to the value of this paper as a review of pregnancy-related LBPP, they argue studies of interactions of risk factors will be fruitful.
Searching PubMed for the most recent (2022 or later) literature on interactions, motor control, and muscles with lumbopelvic pain and pregnancy found several studies about musculoskeletal adaptation during pregnancy and pain. Papers that did not consider pelvic pain or musculoskeletal structure (including exercise interventions) were not considered. There have been attempts to map changes in musculature and lumbopelvic alignment in detail during and after pregnancy (2, 4–6). Interactions with age and disability and muscular strength in areas of the pelvic region are strongly correlated with pelvic pain during pregnancy, but musculature was not predictive (6). However, Palsson et al. found that deep tissue muscle sensitivity during pregnancy was independent of pain (7). There have been limited recently published studies since the Daneau paper to resolve the controversies around exercise as an intervention (8, 9), and it is difficult to separate the effect of exercise from effects of participants disliking exercise (10). Overall, there is not yet enough literature to evaluate the hypothesis of motor adaptations during pregnancy as a major contributor to LBPP. Future studies are needed to conclude the causal relationship and new contributors for LBPP.
Intervertebral disc (IVD) degeneration
Intervertebral disc (IVD) degeneration is significantly increased after menopause (11) and after hysterectomy (12). There is significant mechanistic evidence from human studies that alterations in estrogen could contribute to IVD (13–15). Dissection of mechanisms and possible interventions may be accelerated by studying rodent models, but, in addition to normal problems correlating human and animal models, there is the obvious problem that humans are large bipeds and rodents are small quadrupeds, which leads to very different IVD stresses.
Rodent models of IVD
Lower back pain (LBP) is a common disability, and IVD degeneration is a major cause of LBP. In an extensive review with highlights including sex differences, Tang et al. discuss using mouse models to study IVD degeneration. Despite large differences in mouse and human anatomy, they argue mouse IVD morphology, physiology, and behavior is more similar to humans than dissimilar. Aged and “accelerated aging” mouse models are broadly similar to humans including changes in IVD morphology and inflammatory factors. However, intervention efficacy period coincides with mice beginning to die of old age. Mechanical models (IVD puncture, forced bipedal posture, etc.) can be used on younger mice, but work best on lumbar-level IVDs. The review extensively assesses what has been learned from mouse models of IVD. The authors argue standardization in scoring phenotypes could advance assessment of mouse models by making different studies more comparable. The authors identify several common mouse pain assays that are consistent both between mouse studies and with human behavior, discuss how they determine consistency, and discuss why inconsistencies may occur.
The review ends with a discussion of how to assess the best mouse model for a given clinical or mechanistic question about IVD. The authors have contributed an extensive review of mouse IVD models, their advantages and limitations, and make an argument for the most useful aspects of mouse models of IVD.
Rat models have been extensively studied for anatomical and cellular changes but much less in behavior assays. Barbe et al. compared a 2 lumbar intervertebral disc (IVD) puncture (DP-2) and one lumbar IVD puncture (DP-1) to sham surgery female rats as part of an effort to further develop an animal model for study acute to chronic lower back pain (LBP). The paper extensively compares their results to similar papers. They performed a battery of behavior, serum, and post-mortem histological and morphological assays. To the authors' knowledge, this study provides the most extensive set of behavioral testing of this model in the literature.
Searching PubMed for recent (2022 or later) literature on mouse and rat models of IVD degeneration, excluding those which did not study behavior tests, show limited standardization of behavioral tests for mice (16–19) or rats (20–35). More papers used rat models than mouse models. 70% of papers used von Frey on the paws to test mechanical sensitivity, but no other test was used more than 30% of the time (measurements of various behaviors in the open field test). The most translatable and consistent across models behavior tests identified by Tang et al., grip force, tail suspension, and cold allodynia, were assessed in 50, 100, and 75% of mouse papers, respectively. These were rarely assessed for rats, however (21, 7, and 7%). A fourth of the papers described a new model or refinement of an existing model without new interventions. All papers looked at some gross anatomical measurements of IVD. Many looked at molecular or cellular-level anatomical changes (e.g., macrophage polarization, neurite sprouting, etc.), but there was no protein, cellular, or other marker used in a majority of papers. Rodent models of IVD degeneration are far from standardization or consensus on the best experimental approaches.
Conclusions
Pain disorders disproportionately affect women and girls (1), but mechanistic studies to allow scientifically informed approaches to pain management have continued to be challenging (1, Daneau et al.). Papers outlined above related to this research topic are part of efforts to study sex differences in musculoskeletal pain using epidemiology and more translatable designs in animal models. This will give us a better understanding of sex-specific mechanisms of pain to improve clinical pain outcomes for women worldwide.
Author contributions
JS: Writing – review & editing, Writing – original draft. YK: Writing – original draft, Writing – review & editing, Conceptualization.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Keogh E. Sex and gender differences in pain: past, present, and future. Pain. (2022) 163(Suppl 1):S108–s16. doi: 10.1097/j.pain.0000000000002738
2. Desgagnés A, Patricio P, Bérubé N, Bernard S, Lamothe M, Massé-Alarie H. Motor control of the spine in pregnancy-related lumbopelvic pain: a systematic review. Clin Biomech (Bristol. (2022) 98:105716. doi: 10.1016/j.clinbiomech.2022.105716
3. Stuge B. Evidence of stabilizing exercises for low back- and pelvic girdle pain – a critical review. Braz J Phys Ther. (2019) 23(2):181–6. doi: 10.1016/j.bjpt.2018.11.006
4. Fukano M, Aisaka K, Nose-Ogura S, Fujii T, Torii S. Progressive changes in lumbopelvic alignment during the three month-postpartum recovery period. Int J Environ Res Public Health. (2022) 19(10):5807. doi: 10.3390/ijerph19105807
5. Kharaji G, ShahAli S, Ebrahimi Takamjani I, Kashanian M, Sarrafzadeh J, Shanbehzadeh S. Ultrasound assessment of the abdominal, diaphragm, and pelvic floor muscles during the respiratory and postural tasks in women with and without postpartum lumbopelvic pain: a case-control study. Int Urogynecol J. (2023) 34(12):2909–17. doi: 10.1007/s00192-023-05621-2
6. Sjödahl J, Gutke A, Öberg B. Predictors for long-term disability in women with persistent postpartum pelvic girdle pain. Eur Spine J. (2013) 22(7):1665–73. doi: 10.1007/s00586-013-2716-6
7. Palsson TS, Beales D, Slater H, O’Sullivan P, Graven-Nielsen T. Pregnancy is characterized by widespread deep-tissue hypersensitivity independent of lumbopelvic pain intensity, a facilitated response to manual orthopedic tests, and poorer self-reported health. J Pain. (2015) 16(3):270–82. doi: 10.1016/j.jpain.2014.12.002
8. Daneau C, Marchand AA, Bussières A, O’Shaughnessy J, Ruchat SM, Descarreaux M. Effects of a motor control exercise program on lumbopelvic pain recurrences and intensity in pregnant women with a history of lumbopelvic pain: a study protocol for a randomized controlled feasibility trial. Pilot Feasibility Stud. (2022) 8(1):65. doi: 10.1186/s40814-022-01024-0
9. Yıldırım P, Basol G, Karahan AY. Pilates-based therapeutic exercise for pregnancy-related low back and pelvic pain: a prospective, randomized, controlled trial. Turk J Phys Med Rehabil. (2023) 69(2):207–15. doi: 10.5606/tftrd.2023.11054
10. Koca TT, Özer A. Low back pain and kinesiophobia in pregnant women. J Back Musculoskelet Rehabil. (2024) 37(5):1373–80. doi: 10.3233/bmr-240006
11. Wang YXJ. Postmenopausal Chinese women show accelerated lumbar disc degeneration compared with Chinese men. J Orthop Translat. (2015) 3(4):205–11. doi: 10.1016/j.jot.2015.09.001
12. Zhang Y, Chen X, Yang X, Wang S, Tian Y, Yuan S, et al. Hysterectomy-a possible risk factor for operative intervention in female patients for degenerative lumbar spine conditions: a case control and cohort study. Spine J. (2024) 24(11):2066–77. doi: 10.1016/j.spinee.2024.06.019
13. Baron YM, Brincat MP, Galea R, Calleja N. Intervertebral disc height in treated and untreated overweight post-menopausal women. Hum Reprod. (2005) 20(12):3566–70. doi: 10.1093/humrep/dei251
14. Chen H, Zhu H, Zhang K, Chen K, Yang H. Estrogen deficiency accelerates lumbar facet joints arthritis. Sci Rep. (2017) 7(1):1379. doi: 10.1038/s41598-017-01427-7
15. Chen MH, Hu CK, Chen PR, Chen YS, Sun JS, Chen MH. Dose-dependent regulation of cell proliferation and collagen degradation by estradiol on ligamentum Flavum. BMC Musculoskelet Disord. (2014) 15:238. doi: 10.1186/1471-2474-15-238
16. Huang Y, Lei L, Zhu J, Zheng J, Li Z, Wang H, et al. Pain behavior and phenotype in a modified anterior lumbar disc puncture mouse model. JOR Spine. (2024) 7(1):e1284. doi: 10.1002/jsp2.1284
17. Song XX, Jin LY, Li Q, Li XF, Luo Y. Estrogen receptor Β/substance P signaling in spinal cord mediates antinociceptive effect in a mouse model of discogenic low back pain. Front Cell Neurosci. (2022) 16:1071012. doi: 10.3389/fncel.2022.1071012
18. Tang SN, Salazar-Puerta AI, Heimann MK, Kuchynsky K, Rincon-Benavides MA, Kordowski M, et al. Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain. Biomaterials. (2024) 308:122562. doi: 10.1016/j.biomaterials.2024.122562
19. Vincent KF, Bundock J, Dona CPG, Chenna SS, Mohanty S, Saini C, et al. Loss of lumbar disc height with age and its impact on pain and sensitivity associated behaviors in mice. Eur Spine J. (2023) 32(3):848–58. doi: 10.1007/s00586-023-07545-3
20. Hu Y, Zhao X, Chen M, Zhou F, Zhang X, Chen C, et al. Massage ameliorates lumbar disc herniation-related radicular pain in rats by suppressing Tlr4/Nlrp3 inflammasome signaling transduction. J Orthop Surg (Hong Kong). (2024) 32(1):10225536241238638. doi: 10.1177/10225536241238638
21. Huang Y, Wang L, Luo B, Yang K, Zeng X, Chen J, et al. Associations of lumber disc degeneration with paraspinal muscles myosteatosis in discogenic low back pain. Front Endocrinol (Lausanne). (2022) 13:891088. doi: 10.3389/fendo.2022.891088
22. Koo YW, Lim CS, Darai A, Lee J, Kim W, Han I, et al. Shape-memory collagen scaffold combined with hyaluronic acid for repairing intervertebral disc. Biomater Res. (2023) 27(1):26. doi: 10.1186/s40824-023-00368-9
23. Lee FS, Cruz CJ, Allen KD, Wachs RA. Gait assessment in a female rat sprague dawley model of disc-associated low back pain. Connect Tissue Res. (2024) 65(5):407–20. doi: 10.1080/03008207.2024.2395287
24. Li J, Li H, Chen Y, Bei D, Huang B, Gan K, et al. Induction of cervical disc degeneration and discogenic pain by low concentration Propionibacterium Acnes infection: an in vivo animal study. Arthritis Res Ther. (2024) 26(1):41. doi: 10.1186/s13075-024-03269-x
25. Lillyman DJ, Lee FS, Barnett EC, Miller TJ, Alvaro ML, Drvol HC, et al. Axial hypersensitivity is associated with aberrant nerve sprouting in a novel model of disc degeneration in female sprague dawley rats. JOR Spine. (2022) 5(3):e1212. doi: 10.1002/jsp2.1212
26. Maruyama T, Nakamae T, Kamei N, Morisako T, Nakao K, Farid F, et al. Development of a novel animal model of lumbar vertebral endplate lesion by intervertebral disk injection of monosodium iodoacetate in rats. Eur Spine J. (2024) 33(5):2116–28. doi: 10.1007/s00586-024-08179-9
27. Mohd Razak R, Harizal NAA, Azman MAZ, Mohd Redzuan NS, Ogaili RH, Kamarrudin AH, et al. Deciphering the effect of hyaluronic acid/collagen hydrogel for pain relief and tissue hydration in a rat model of intervertebral disc degeneration. Polymers (Basel). (2024) 16(18):2574. doi: 10.3390/polym16182574
28. Morisako T, Nakamae T, Kamei N, Tamura T, Tsuchikawa Y, Harada T, et al. Development of a rat model with lumbar vertebral endplate lesion. Eur Spine J. (2022) 31(4):874–81. doi: 10.1007/s00586-022-07148-4
29. Niu L, Zuo CJ, Zhang YL, Ma CX, Zhou XW, Sun SR, et al. Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats. Neurochem Int. (2024) 177:105764. doi: 10.1016/j.neuint.2024.105764
30. Peng Y, Chen X, Rao Z, Wu W, Zuo H, Chen K, et al. Multifunctional annulus fibrosus matrix prevents disc-related pain via inhibiting neuroinflammation and sensitization. Acta Biomater. (2023) 170:288–302. doi: 10.1016/j.actbio.2023.08.028
31. Stover JD, Trone MAR, Weston J, Lewis C, Levis H, Farhang N, et al. Therapeutic crispr epigenome editing of inflammatory receptors in the intervertebral disc. Mol Ther. (2024) 32(11):3955–73. doi: 10.1016/j.ymthe.2024.09.022
32. Suzuki H, Ura K, Ukeba D, Suyama T, Iwasaki N, Watanabe M, et al. Injection of ultra-purified stem cells with sodium alginate reduces discogenic pain in a rat model. Cells. (2023) 12(3):505. doi: 10.3390/cells12030505
33. Wang D, Lai A, Gansau J, Seifert AC, Munitz J, Zaheer K, et al. Lumbar endplate microfracture injury induces modic-like changes, intervertebral disc degeneration and spinal cord sensitization - an in vivo rat model. Spine J. (2023) 23(9):1375–88. doi: 10.1016/j.spinee.2023.04.012
34. Wawrose RA, Couch BK, Dombrowski M, Chen SR, Oyekan A, Dong Q, et al. Percutaneous lumbar annular puncture: a rat model to study intervertebral disc degeneration and pain-related behavior. JOR Spine. (2022) 5(2):e1202. doi: 10.1002/jsp2.1202
Keywords: chronic pain, women in science, pain, musculoskeletal pain, lumbopelvic pain, intervertebral disc (IVD) degeneration, pregnancy-related lumbopelvic pain
Citation: Shannonhouse J and Kim YS (2025) Editorial: Women in science: musculoskeletal pain. Front. Pain Res. 6:1599967. doi: 10.3389/fpain.2025.1599967
Received: 25 March 2025; Accepted: 26 March 2025;
Published: 28 April 2025.
Edited and Reviewed by: Ke Ren, University of Maryland, United States
Copyright: © 2025 Shannonhouse and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yu Shin Kim, a2lteTFAdXRoc2NzYS5lZHU=