# Meningeal prolactin signaling and female-selective migraine mechanisms

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2020 · $477,461

## Abstract

Women consistently report higher headache-related disabilities, higher relapse rate, more frequent, longer
lasting, and more severe headaches than men. Hence, there is an urgent need to customize migraine
management schemes based on sex-specific pain mechanisms. Accordingly, our long-term goal is to
define sex-specific mechanisms of migraine, and utilize this knowledge to provide more effective sex-
based personalized migraine management schemes.
It is well accepted that the pathogenesis of headache syndromes, especially migraine, are sex-dependent
due to important contributions of gonadal hormones (GnH). First, some reports show that migraine attacks
in female and males are accompanied by a rise in plasma levels of prolactin (PRL). Second, we and
others demonstrated that PRL responsiveness in pain pathways is sex-dependent and strictly controlled
by estrogen. There is a critical gap in knowledge pertaining to whether and how the PRL system sex-
dependently regulates migraine. The objective of this proposal is to identify mechanisms linking the PRL
system to stress- and sex-dependent regulation of certain types of migraine. Our preliminary data
demonstrate that PRL applied to cranial dura induces long-lasting facial allodynia in females, but not
males. PRL also sensitizes mustard oil-evoked CGRP release from female, but not male dura. Finally, to
further link the PRL system to migraine, we showed that a PRL receptor (Prlr) antagonist blocks CGRP-
induced migraine behavior in females. Thus, our central hypothesis is that PRL acting through the Prlr
on dural-innervating sensory neurons mediates female-specific mechanisms contributing to
migraine. The rationale for the proposed study is that it 1) greatly expands our knowledge of sex
differences in migraine mechanisms; and 2) provides translational potential by offering therapeutic targets
for sex-based migraine management. Our hypothesis is tested by interconnected yet independent aims.
Aim 1 examines sex-specific expression and regulation of PRL and Prlr in the trigemino-vascular system.
Aim 2 determines how PRL and Prlr sex-specifically modulate the activity of dural afferents and migraine-
like behavior in stress-induced migraine models. Aim 3 assesses a link between CGRP-induced migraine
behavioral responses and the dural PRL system. The proposed study is innovative since it defines
conceptually novel sex-specific regulatory mechanisms for certain migraine models based on PRL
signaling. The proposed research is significant as it advances our understanding of sex differences in
migraine mechanisms – an understudied area where increasing basic science knowledge has the potential
to lead to better sex-based personalized therapeutics.

## Key facts

- **NIH application ID:** 9993620
- **Project number:** 5R01NS104200-03
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** ARMEN N AKOPIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,461
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993620

## Citation

> US National Institutes of Health, RePORTER application 9993620, Meningeal prolactin signaling and female-selective migraine mechanisms (5R01NS104200-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993620. Licensed CC0.

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