Lifestyle Triggers Of Migraine: Sex-Specific Effects of Sleep Restriction & Caffeine in Rats

A recent study published in Headache: The Journal of Head and Face Pain, Lifestyle Triggers Of Migraine: Sleep Restriction And Caffeine Lower The Threshold For Migraine-Like Responses In Rats In A Sex-Specific Manner,” led by Gabriel Camargo de Oliveira, DDS, explores the effects of sleep restriction and caffeine intake in isolation and in combination on migraine susceptibility in male and female rats. 

Even though epidemiological and clinical studies have identified a bidirectional link between migraine and insufficient sleep and a complex, bidirectional role of caffeine on migraine, the effects of caffeine on migraine under sleep-deprived conditions remained unexplored. “We tried to see the interaction of caffeine, which is one of the most used illicit drugs in the world, and how it interacts with sleep restriction, that we know that's very common in the actual data and population,” said senior author Juliana Chichorro, PhD. “We want to see if this interaction could increase the susceptibility of migraine, and also we want to see if there was some sex difference in these responses.”

Watch the full discussion with Dr. Chichorro:

Using a gentle handling method, researchers subjected the Wistar rats to sleep restrictions over three consecutive days, and then exposed the rats to one of two migraine-inducing peptides: calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Researchers then evaluated whether the sleep loss enhanced susceptibility to migraine-like response. Following independent sleep restriction testing, researchers examined the impact of the three days of caffeine intake on the development of migraine-like response in both sleep-restricted and well-rested rats.

Findings revealed that sleep restriction alone did not induce migraine-like pain in either male or female rats, but sleep restriction combined with migraine-inducing peptides provoked migraine-like responses in female rats alone. In well-rested rats, the three-day caffeine regimen paired with CGRP or PACAP only elicited migraine-like responses in females. Furthermore, both male and female sleep-restricted rats who received caffeine and the migraine-inducing peptides developed migraine-like responses — with female rats seeing amplified responses.

These results suggest that sleep restriction renders female rats more susceptible to migraine-like responses when exposed to migraine-inducing peptides, but not male rats. “We actually don't know if males are fully resistant or if we increase the doses, for example, for CGRP or PACAP…but they are more resistant than females,” said Dr. Chichorro.

The results also indicate that caffeine enhances the effects of the interaction, as it led to robust migraine-like responses in both sexes, but a longer-lasting response in females. “So caffeine is a modulator of the trigeminovascular system in a way that we don't know yet, but this combination in females caused a greater response. So they are more sensitive to the CGRP or PACAP when a sleep restriction is combined with caffeine,” added Dr. Chicorro.

Headache publishes original clinical and basic research on head and face pain, aiming to advance understanding and care of headache medicine. This study adds to and validates the growing body of studies exploring how sleep loss contributes to migraine development in susceptible individuals. The study also lays the groundwork for future research examining combined effects of caffeine intake, poor sleep, and migraine-related outcomes across human or animal subjects.

While the animal study cannot provide direct translations for human populations, Dr. Chichorro believes clinicians can still utilize these valuable insights. “This association maybe is a trigger for some patients to take a lot of caffeine, [when they do] not have a good sleep,” said Dr. Chichorro. “I think the main message right now is to pay attention to the patient and [their] habits and everything to see if this may complicate the situation… caffeine intake, worse sleep, and all the habits that the patient may present.”

Looking ahead, Dr. Chichorro notes that there is still more research to be done to understand the female and male mechanisms related to migraine and these triggers and whether interventions targeting sleep quality and caffeine consumption can mitigate these risks in susceptible populations.

This research validates not only other preclinical and clinical studies, but also the anecdotes among patients and clinicians as they navigate migraine management and treatment. It also underscores the need for research aimed at understanding underlying sex differences in migraine, especially for women, and can help clinicians develop more personalized treatment strategies and lifestyle modifications.

Read the Full Transcript

Dr. Rashmi Halker Singh:

I'm Dr. Rashmi Halker Singh. I'm the deputy editor of Headache. It's my pleasure today to be joined by Dr. Juliana Chichorro, who's one of the authors of a recent publication entitled “Lifestyle Triggers of Migraine: Sleep Restriction and Caffeine Lower the Threshold for Migraine-like Responses in Rats in a Sex-Specific Manner”. Welcome, Dr. Chichorro. It's so nice to speak with you about your work.

Dr. Juliana Chichorro:

Thank you very much for having me here.

Dr. Rashmi Halker Singh:

So first of all, your study looks at two very common lifestyle factors, sleep restriction and caffeine, and how they influence migraine biology. What motivated your team to explore this specific interaction?

Dr. Juliana Chichorro:

So in this study, we tried to see the interaction of caffeine, which is one of the most used illicit drugs in the world, and how it interacts with sleep restriction that we know that's very common in the actual dates and population. So we want to see if this interaction could increase the susceptibility of migraine, and also we want to see if there was some sex difference in these responses.

Dr. Rashmi Halker Singh:

Yeah, I think that's very interesting. One of the concepts that you talked about in your paper was lowering the threshold for migraine-like responses. Can you explain that a little bit?

Dr. Juliana Chichorro:

So in this study, we used a protocol of sleep restriction where we use a gentle handling method that there's no stress involved. We prevent the animals from sleeping for three consecutive days, male and females, and then we expose them to non-mediators of migraine, which are CGRP and  PACAP. And we saw that when we do this protocol, combined protocol with sleep restriction plus CGRP injection, we provoked migraine-like responses in females, but not in males, suggesting that males are more resistant to develop migraine-like responses when they are subjected to these different triggers. And then we want to add caffeine in this story because we know that caffeine is very useful when you are sleepy and you take this every day for many reasons. And when you combine caffeine and sleep restriction, then we saw a response in males. So caffeine is a modulator of the trigeminovascular system in a way that we don't know yet, but this combination in females caused a greater response. So they are more sensitive to the CGRP or  PACAP when a sleep restriction is combined with caffeine.

Dr. Rashmi Halker Singh:

I think that's very interesting, and I want to go back to something you said. You shared that a major finding in the study was that sleep restriction increased susceptibility to migraine-like responses in the female rats, but not in the male rats. Why do you think there's a sex-specific difference in this vulnerability?

Dr. Juliana Chichorro:

We actually don't know if males are fully resistant or if we increase the doses, for example, for CGRP or  PACAP, they're going to show a response. But in this protocol, we only saw nociceptive responses in females, suggesting that females are more sensitive to sleep restriction plus caffeine plus CGRP and PACAP. However, the association of CGRP or  PACAP and sleep restriction and caffeine in males also provoked the nociceptive response. So I would say that this combination is not good for migrainers, and there's a sex difference. I believe that mainly in the sensitivity, than the response at all. Males can develop this response, but they are more resistant than females. And the reason why this happened, we don't know. We have to explore, to work more on that to try to understand these differences.

Dr. Rashmi Halker Singh:

So that's future work, basically.

So your study was mainly done on rats, but as a physician who takes care of human patients, what can I take from your work and how do I apply this to my human patients?

Dr. Juliana Chichorro:

So it's very complicated to have a direct translation now for humans because we know that there are many differences between species, but we can say that you can pay attention to the patient habits, intake of caffeine, how much he intakes. Sleep is very important for migrainers. So this association may be the trigger for some patients — to take a lot of caffeine, to not have a good sleep. Maybe it's the main reason for increasing the attack frequency or the severity of the crisis. So we are just starting this work, so there's much to do and much to know about it. But I think the main message right now is to pay attention to the patient and his habits and everything to see if this may complicate the situation, this may worsen the condition. Caffeine intake, worse sleep, and all the habits that the patient may present.

Dr. Rashmi Halker Singh:

I think your study's very interesting and validates many of the things that our patients share with us. So I really appreciate the work you're doing, and I look forward to more research from you and your team. Thank you so much for taking the time to speak with me today.

Dr. Juliana Chichorro:

Thank you so much.