We all know someone who claims hugs are the best kind of medicine. While that might not sound wise if you meet Huggy Bear in the woods, there could be some truth to the adage. Experts are investigating whether the ‘love hormones’, oxytocin and prolactin, may be the key to unlocking migraine pain and prevention.
Honey, I’ve Got a Headache
Medical research typically looks to male bodies for clues to medical mysteries, but in this case, it’s the female body that might hold the answers. Most of us have heard the old jokes about men whose wives seem to have a permanent headache. Although most of those headaches might have been caused by being married to the kind of man who cracks wise about your headaches, it is a fact that migraines attack women at a greater frequency than men.
Migraines are a complex neurological disorder that affects numerous regions of the brain. According to the Global Burden of Disease Study 2019, migraine is the second most common cause of disability for men and women worldwide. Women between the ages of 15 and 49 are three times more likely to be struck down by a debilitating migraine.
Could female sex hormones be the culprit? At first it might appear that sex differences in migraine are just another spanner in the works adding complexity to this already confusing condition. What, however, if this sex difference creates an entry point for scientists to figure out what is causing the pain, and how to counteract it?
What’s so special about love hormones?
Researchers are always brainstorming new ways to treat the pain associated with migraine. But you may be asking, how did they land on the cuddle chemicals?
Coined the ‘love hormone’, oxytocin is famously associated with social bonding and relationship building. Oxytocin is released by the brain during skin-skin contact. The idea is that when you get close to another person, oxytocin is released and makes you feel good. One of the most striking examples of its power is its ability to make childbirth bearable. At the height of labour, when contractions are strongest, oxytocin reaches a critical threshold in the brain and triggers a flood of endorphins. Endorphins are the ‘happy hormones’ that give you that rush after exercise or tasting something spicy. This natural coping mechanism led scientists to wonder, if it works on childbirth, could it also ease the symptoms of a migraine?
When researchers looked into the link between oestrogen, pregnancy and women’s propensity for migraines, they found that migraine attacks seemed to correspond to dips in oestrogen levels. This caught scientist’s attention because a woman’s oxytocin levels rise and fall with her oestrogen levels. What’s more, in an intriguing twist, researchers have noticed that pregnancy is a time marked by fewer migraines.
This isn’t the first-time scientists have put forward oxytocin as a potential pain reliever. Studies have even linked low levels of the hug hormone with abdominal and back pain. It certainly sounds like the evidence stacking up in oxytocin’s favour!
Prolactin’s Potential
The other cuddle chemical that migraine detectives picked up on, was prolactin. Prolactin is the hormone that activates milk production in new mothers and enhances dad-baby bonding in new fathers. Importantly, it also promotes testosterone homoeostasis. Following this train of thought, we can see how prolactin plays a role in male fertility and spermatogenesis.
Surprisingly, prolactin also shows up at unusually high levels in the blood of migraine sufferers. Further work has linked the onset of a migraine attack to a rise in prolactin hormone levels. So, drops in oxytocin and rises in prolactin go hand in hand with migraine.
Brain Science
Despite the uncertainty surrounding its origin, scientists have flagged the ‘trigeminovascular system’ (TVS) as a potential birthplace for our headaches. The TVS is a cluster of sensory neurons within the trigeminal nerve. This is one of the nerves responsible for providing sensation to the face. Scientists believe that changes in neurons of the TVS trigger migraine pain.
When they investigated whether prolactin was active in the TVS, they found that it 1) stimulates neurons to fire when they shouldn’t, 2) releases CGRP – the protein that many existing migraine treatments target and 3) intensifies sensations detected by TRPV1 channels. These are all the hallmarks of a headache.
Interestingly, when neuroscientists looked into how oxytocin works on the brain, they discovered that it has the opposite effect on neurons to prolactin! In healthy individuals, prolactin levels are balanced with oxytocin. However, for migraine sufferers the scale appears to tip towards prolactin. This has prompted doctors to question whether tweaking this balance in favour of oxytocin could calm the sensitive TVS nerves and prevent the development of migraine.
Hitting Migraine Where It Hurts
So, how do we convert this information into an anti-migraine drug? Hypothetically, a drug that blocks prolactin could prevent migraine-associated pain. Scientists have also thrown around the idea of monoclonal antibodies targeting prolactin. However, since prolactin plays an important role in regulating sex hormones, any drug will need to focus only on the pain-causing function of prolactin. A prolactin blocking drug would have to be applied directly to the affected neurons rather than come in a pill form. Researchers are looking into overcoming this hurdle by developing locally applied treatments such as nasal sprays.
Another avenue is to repurpose existing drugs that target prolactin. Scientists discovered that dopamine release can switch off prolactin in the brain. When they investigated further, they found that the dopamine releasing drug bromocriptine can reduce prolactin levels in mice with migraines.
Going down the oxytocin-enhancing route, scientists are particularly interested in delivering this hormone intranasally via nasal spray. This method will reduce off-target side effects and ensure rapid brain delivery.
Migraine Mitigation
We may not be waiting long for an oxytocin powered migraine mitigator. Tonix Pharmaceuticals have an oxytocin based nasal spray in trials right now. This phase two clinical trial will investigate how well the nasal spray drug TNX-1900 is at preventing symptoms in chronic migraine patients. Another trial by Danish researchers pits the existing prolactin targeting drug, dostinex (cabergoline) against migraine. Right now the researchers are analysing the results of a randomized controlled trial that tested cabergoline’s ability to prevent chronic migraine over a twelve-week period.
Migraine mechanisms might still be mysterious, but what we do know is that prolactin and oxytocin are a corner piece of this perplexing puzzle.
References
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A study to evaluate the efficacy and safety of TNX-1900 in patients with chronic migraine – full text view. ClinicalTrials.gov. Accessed May 3, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05679908.
Cabergoline as a preventive treatment for chronic migraine – full text view. ClinicalTrials.gov. Accessed May 3, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05525611.
