Ectopic uterine tissue as a chronic pain generator
Open accessAbstract
While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the exploration of ectopic endometrium as a source of endometriosis pain. Rats were surgically implanted with autologous uterus in the gastrocnemius muscle. Within two weeks, visual inspection revealed the presence of a reddish-brown fluid-filled cystic structure at the implant site. Histology demonstrated cystic glandular structures with stromal invasion of the muscle. Immunohistochemical studies of these lesions revealed the presence of markers for nociceptor nerve fibers and neuronal sprouting. Fourteen days after surgery rats exhibited persistent mechanical hyperalgesia at the site of the ectopic endometrial lesion. Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic. Systemic administration of leuprolide also produced antihyperalgesia. In vivo electrophysiological recordings from sensory neurons innervating the lesion revealed a significant increase in their response to sustained mechanical stimulation. These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain. This model of endometriosis allows mechanistic exploration at the lesion site facilitating our understanding of endometriosis pain.
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In a rat model of autotransplantation of endometrium to the gastrocnemius muscle, cystic lesions developed within 2 weeks with stromal invasion of the muscle, nociceptor nerve fibers, and neuronal sprouting, and persistent mechanical hyperalgesia at the site of the lesions.
“In a rat model of autotransplantation of endometrium to the gastrocnemius muscle, cystic lesions developed within 2 weeks with stromal invasion of the muscle, nociceptor nerve fibers, and neuronal sprouting, and persistent mechanical hyperalgesia at the site of the lesions.89”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [89]
In vivo electrophysiological recordings from sensory neurons innervating the lesions revealed a significantly increased response to sustained mechanical stimulation.
“This is the first model to record in vivo electrophysiological recordings from sensory neurons innervating the lesions which revealed a significantly increased response to sustained mechanical stimulation.89”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [89]
These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain.
“These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain.”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [89]
Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic as was systemic administration of leuprolide.
“Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic as was systemic administration of leuprolide.”
From Defining Future Directions for Endometriosis Research: Workshop Report From the 2011 World Congress of Endometriosis in Montpellier, France (2013) · cites this paper as [89]
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Rogers, P. A. W., D’Hooghe, T. M., Fazleabas, A., Giudice, L. C., Montgomery, G. W., Petraglia, F., & Taylor, R. N. (2013) · Reproductive Sciences · doi:10.1177/1933719113477495 · Cited by 154 · see citing works
Self-citationvan Aken, M., Oosterman, J., van Rijn, T., Woudsma, K., Ferdek, M., Ruigt, G., Kozicz, T., Braat, D., Peeters, A., & Nap, A. (2018) · Fertility and Sterility · doi:10.1016/j.fertnstert.2018.06.040 · Cited by 26 · see citing works
- Authors
- Alvarez, P., Chen, X., Hendrich, J., Irwin, J. C., Green, P. G., Giudice, L. C., & Levine, J. D.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Levine, J.D.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 225
- Pages
- 269-282
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC3479308
- OpenAlex
- W2064456534
- Cited by
- 39
- References
- 64
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 7 · 2013: 6
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P01NS053709)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR063312, R01AR054635)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- endometriosis, ectopic endometrium, chronic pain, mechanical hyperalgesia, animal models, nerve sprouting, progesterone, leuprolide, sensory neurons
- MeSH terms
- Amifampridine, Action Potentials, Animals, Biophysics, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Electric Stimulation, Endometriosis, Endometrium, Female, Ganglia, Spinal, Hyperalgesia, Nerve Fibers, Progestins, Progesterone, Sensory Receptor Cells, Time Factors, Uterus, Calcitonin Gene-Related Peptide, 4-Aminopyridine, Leuprolide, Rats, Sprague-Dawley, Patch-Clamp Techniques, Muscle, Skeletal, Antineoplastic Agents, Hormonal, Transplants, Tetraethylammonium, GAP-43 Protein, Potassium Channel Blockers, Estrous Cycle, Lectins, Rats, Chronic Pain
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