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5 Articles in this Series
Introduction
Diet “Cheat” Days Negatively Impact Recovery From Inflammatory Injury
Ketogenic Diet Prevents and Rescues Mechanical Allodynia Induced by a High Fat Diet
Prolactin Linked to Sex Differences in Migraine
Toward Automated Pain Intensity Estimation in Mice: Finding Structure in Complex Data
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Prolactin Linked to Sex Differences in Migraine

Presentation by Greg Dussor, PhD

Migraine is the third most common disease in the world and affects roughly 1 in 7 people.1 It significantly affects quality of life, yet only half of sufferers experience pain relief with the currently available treatments.

Migraines are 2 to 3 times more common in women than men.

One of the mysteries of the disease is that migraine is 2 to 3 times more prevalent in women than men.2 Hormones are thought to play a role in this dichotomy for several reasons. Migraines appear with equal frequency in boys and girls before puberty; are most common during reproductive years yet generally improve with pregnancy and menopause; and half of women with migraines get them during specific times in their menstrual cycle.3,4

Studies have shown that migraineurs have elevated serum levels of calcitonin gene related peptide (CGRP)5 and prolactin,6 which can both be modulated by female sex hormones. New research7 presented at this year’s meeting examined the role that CGRP and prolactin can play in the observed sex differences of migraine. The research was selected as one of the meeting’s most promising abstracts by the Scientific Program Committee and was therefore presented as both a poster and a talk in a session of meeting highlights.

To model migraine pain, the researchers injected the proinflammatory cytokine interleukin 6 (IL-6) onto the dura mater to produce acute periorbital hypersensitivity and paw sensitivity in both sexes of mice. The mice recovered within 72 hours, but became sensitized so that later treatment with an otherwise innocuous stimulus (pH 7.0 solution) was noxious. Control animals not exposed to IL-6 were not affected by pH 7.0.

In contrast, applying prolactin to the dura produced facial and hindpaw hypersensitivity and grimacing only in female mice, an effect that persisted for at least 7 days. Male mice showed no effect. “This is about as obvious of a sex difference as I’ve ever seen, even in the literature,” said lead study author Greg Dussor, PhD, associate professor at the University of Texas Dallas.

The researchers next uncovered a potential explanation for sex-specific sensitization to prolactin, finding that the prolactin receptor was expressed in the nerve fibers of the dura in female but not male mice.

Dussor and colleagues then removed the dura and examined CGRP release following the administration of mustard oil. Prolactin potentiated CGRP release in females but not males.

The researchers also showed that stress, a known migraine trigger in humans, produced acute hypersensitivity as well as a sensitization of mice to both pH 7.0 as well as the nitric oxide donor sodium nitroprusside. Interestingly, the 3 days of restraint stress increased serum prolactin levels in females but not males.

The researchers are currently examining the effect of prolactin on stress-induced hypersensitivity using mice in which the prolactin receptor has been deleted from sensory neurons, Dr. Dussor noted.

Application of CGRP on the dura also produced a sex-specific effect. CGRP produced acute hypersensitivity and priming to pH 7.0 only in female mice. This effect was blocked by concomitant dural administration of a prolactin receptor antagonist.

“Our results show that there is some sort of crosstalk between the prolactin and CGRP systems that we don’t yet understand,” said Dr. Dussor. He hypothesized that the interaction occurs between nerve endings releasing CGRP in the dura and nearby blood vessels that synthesize prolactin.

The new study suggests not only that prolactin contributions to migraine may underlie the increased prevalence of migraines in women compared to men, but also points to the possible therapeutic efficacy of drugs targeting prolactin signaling for female migraineurs.

 

References

1.     Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. J Headache Pain. 2013;14(1):1.

2.     Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

3.     Couturier EG, Bomhof MA, Neven AK, van Duijn NP. Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia. 2003;23(4):302-308.

4.     Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. Journal Headache Pain. 2012;13(3):177-189.

5.     Edvinsson L. The Trigeminovascular Pathway: Role of CGRP and CGRP receptors in migraine. Headache. 2017;57 Suppl 2:47-55.

6.     Bosco D, Belfiore A, Fava A, De Rose M, Plastino M, Ceccotti C, Mungari P, Iannacchero R, Lavano A. Relationship between high prolactin levels and migraine attacks in patients with microprolactinoma. J Headache Pain. 2008;9:103-107.

7.     Burgos Vega C, Quigley L, Patel M, Price T, Arkopian A, Dussor G. Meningeal application of prolactin and CGRP produces female specific migraine-related behavior in rodents. Poster presented at: Annual Meeting of the American Pain Society; May 17-20, 2017; Pittsburgh, PA. Poster #137.

 

 

 

 

Next summary: Toward Automated Pain Intensity Estimation in Mice: Finding Structure in Complex Data
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