Background & Aims

Endometriosis is a gynecological disease that is associated with chronic pelvic pain and infertility. For reasons that are not well understood, there is a high comorbidity between endometriosis and migraine. We reasoned that endometriosis and migraine may share common underlying mechanisms. Prolactin (PRL) is a neurohormone released into circulation from the pituitary and could also be produced locally by endometrium. PRL is clinically associated to both endometriosis and migraine. Exogenous PRL sensitizes mouse trigeminal ganglion and dorsal root ganglion (DRG) neurons in a female-selective manner. Importantly, PRL also sensitizes human DRG neurons from female donors only. PRL signals through prolactin receptor isoforms, long(PRLR-L) and short (PRLR-S). Signaling at PRLR-L has been shown to promote gene transcription, while PRLR-S elicits pronociceptive effects in females. We hypothesized that systemic or local PRL signaling at PRLR-S may underlie pain in migraine and endometriosis.

Methods

Endometriosis was induced by implantation of uterine tissue fragments from donor mice into intraperitoneal space of recipient female mice. Mice were exposed to a subthreshold dose of umbellulone, a TRPA1 agonist, demonstrated to produce migraine like pain in previously sensitized animals. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was administered daily for 2 weeks, starting 6 weeks post-induction. Pain was accessed weekly using von-Frey filament application on the abdomen and cephalic area. Endometriotic lesions, serum, uterus, DRG and TG were collected for analysis 6-8 weeks post-induction. To examine possible involvement of systemic and local PRL on dysregulation of PRLR isoforms, serum PRL levels were measured with enzyme-linked immunosorbent assay and expression of PRLR isoforms was examined with western blot. Additionally, we accessed excitability of DRG and TG neurons using whole cell patch clamp electrophysiology.

Results

Mice with endometriosis showed persistent abdominal allodynia, but not cephalic allodynia. However, inhalational of a subthreshold dose of umbellulone produced cephalic allodynia, a surrogate measure of migraine-like pain. Umbellulone also increased the excitability of TG neurons cultured from endometriosis, but not sham, mice. Both systemic and local PRL levels in endometriotic lesions were elevated along with upregulation of PRLR-S in TG and DRG neurons from endometriosis mice. Eliminating local PRL by utilizing PRL knockout mice as uterine tissue donors abolished the endometriotic lesion development and endometriosis-associated pelvic pain. Blockage of systemic PRL with cabergoline, a dopamine D2 receptor agonist, did not reverse established endometriosis-associated pelvic pain and did not affect prolactin receptor dysregulation or excitability in DRG neurons. However, cabergoline prevented PRLR-S upregulation and increased excitability of TG neurons as well as umbellulone-induced cephalic allodynia in endometriosis mice.

Conclusions

Our study demonstrates that local PRL from endometriotic lesions may affect endometriotic lesion development and endometriosis-associated pelvic pain while elevated systemic PRL in endometriosis may increase vulnerability to migraine. High systemic and local PRL sensitize sensory neurons through upregulation of PRLR-S expression resulting in endometriosis-associated pelvic pain and migraine-like pain from normally innocuous stimuli. Together, these findings highlight opportunities for treatment in endometriosis and comorbid disorders, including the use of dopamine D2 receptor agonists for migraine and potential development of PRL or PRLR antibodies, which would sequester both local and systemic PRL for treatment of both pelvic pain and migraine.

References

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Presenting Author

Grace Lee

Poster Authors

Grace Lee

MD, PhD

University of Arizona

Lead Author

Veronica Hode

B.S.

University of Arizona

Lead Author

Sasan Behravesh

M.D.

Mayo clinic

Lead Author

Teodora G Georgieva

PhD

University of Arizona

Lead Author

Jill Rau

M.D.

HonorHealth, Scottsdale

Lead Author

David Dodick

M.D.

Atria Academy of Science and Medicine

Lead Author

Frank Porreca

PhD

University of Arizona

Lead Author

Edita Navratolova

PhD

University of Arizona

Lead Author

Topics

  • Specific Pain conditions/Pain in Specific Populations: Gynecological Pain