Starts:

Tuesday, September 20th
4:30pm-6:00pm EDT

Category:

Topical Workshop

Tracks:

Basic Science

Room

711

Mechanisms Leading to the Female-Biased Nature of Migraine: Moving Beyond Estrogen

Migraine is the second leading cause of disability worldwide. Women are disproportionately affected by migraine with prevalence at two- to three-times higher than in men. In women, migraine frequency is highest between puberty and menopause, attacks are often linked to the cycle, frequency of attacks can change across pregnancy, and they are often influenced by the use of oral contraceptives. These patterns strongly implicate hormones in the pathology of migraine but many years of investigation into the effects of estrogen and progesterone have still not led to a clear understanding of how hormones contribute to the disorder. In this workshop, panelists will present data showing that the pituitary hormone prolactin contributes differentially to migraine-related events within the brain and peripheral nervous systems of female and male rodents. Panelists will also present data from rodents on the differences between females and males in effects of calcitonin-gene related peptide (CGRP), the target of new therapeutics. Finally, differential effects of hormone and migraine therapeutic administration to female and male humans will be presented. Together, the data presented will show how events downstream of estrogen may contribute to the female-biased nature of migraine offering up new insights for the development and optimization of therapy.

Presentations

Time
4:30pm EDT6:00pm EDT

Hypothalamic Stress Circuits Regulate Prolactin to Promote Female-Selective Nociceptor Sensitization and Migraine-Like Pain

Tracks: Basic Science
Categories: Topical Workshop

Migraine is a female predominant multiphasic neurological disorder. Imaging studies have demonstrated activation of the hypothalamus in the premonitory phase that often precedes the headache phase in most patients.  Migraines are commonly associated with triggering events that can include external or internal stressors but how these disruptions lead to the headache phase is not known. Prolactin is secreted from the anterior pituitary and acts via a prolactin receptor that is expressed in two main isoforms. Data from preclinical studies will be presented to show that female mice have higher levels of prolactin and increased prolactin responses to stress that can be prevented by blocking stress circuits in the hypothalamus. Additionally, female mice have increased expression of prolactin receptor isoforms in the trigeminal and dorsal root ganglia. Genetic deletion or stress, disrupts the balance of prolactin receptor isoform expression, promoting nociceptor sensitization and migraine-like pain selectively in female mice. Pharmacological inhibition of circulating prolactin prevents nociceptor sensitization and migraine pain selectively in females.  These data demonstrate a female-selective mechanism of nociceptor sensitization and provides a link between external or internal stress responses in the brain and nociceptors, the fundamental building blocks of pain, offering new therapeutic opportunities.

4:30pm EDT6:00pm EDT

Sex-Specific Actions of Multiple Neuropeptides in Preclinical Migraine Models

Tracks: Basic Science
Categories: Topical Workshop

Migraine is a complex disorder consisting of multiple phases and a variety of sensory disturbances. The pain phase of migraine requires activation of nociceptors that innervate the cranial meninges but the events that lead to activation and sensitization of these neurons remain poorly understood. Using preclinical migraine models in rodents, differential expression patterns of prolactin receptors were found between females and males within the meninges and female-specific cellular and behavioral actions of prolactin were observed. Behavioral responses to dural prolactin were only partially attenuated in ovariectomized females. Dural application of CGRP produced female-specific behavioral responses that were dependent on prolactin receptor activation and were completely lost in ovariectomized females. In contrast, dural application of amylin caused male-specific behavioral responses. While normally cycling females had no response to dural amylin, a robust response was observed in ovariectomized females. These data demonstrate that the prolactin, CGRP, and amylin systems within the periphery have differential actions between the sexes and the effects of these peptides is dependent on ovarian-derived hormones. Further, they offer an opportunity to increase mechanistic understanding of the female-biased nature of migraine and identify new approaches for female-specific therapeutics.

4:30pm EDT6:00pm EDT

Sex and Gender-Specific Peripheral Trigeminovascular Actions of CGRP in Migraine

Tracks: Basic Science
Categories: Topical Workshop

While it is known for many years that migraine is more prevalent in women than in men, we recently demonstrated that the acutely acting antimigraine drugs, triptans, have  higher recurrence rates in women. This is likely due to menstruation-dependent migraine attacks which have an increased duration, predisposing to the risk of medication overuse and emphasizing the need to develop female-specific prophylactic treatment. It is becoming increasingly evident that, besides the brain, also the peripheral part of the trigeminal system is differentially regulated between sexes. While administration of exogenous sex steroid hormones affects trigeminovascular responses in rodents, also the human trigeminovascular system and trigeminal pain perception exhibit sex-specific responses and, within females, vary during different hormonal stages.   Further, we recently showed that the trigeminovascular effects of the ß-adrenoceptor antagonist propranolol are male-specific, which seems to fit with a presumably higher clinical efficacy of propranolol in prophylactic migraine treatment in men. A deeper understanding of the mechanisms underlying such sexually dimorphic responses will enable the development of more efficient, gender-specific drugs, but it will also increase the understanding of gender-dependent differences in clinical response to currently available antimigraine drugs.

Presenters

Professor Gregory Dussor

Professor
University of Texas, Dallas

Professor Antoinette Maassen MaassenVanDenBrink

Professor of Neurovascular Pharmacology
Erasmus MC

Professor Frank Porreca

Professor
University of Arizona