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19 Articles in Volume 19, Issue #6
Arthrofibrosis: Targeting Hormones after Childbirth to Relieve Frozen Shoulder, Inflamed Joints
Can CGRP Help Clarify Why Migraine Is More Common in Women?
Case Report: Managing Chronic Pelvic Pain in Men
CGRP Monoclonal Antibodies for Chronic Migraine: Year 1 of Clinical Use
Chronic Pelvic Pain as a Form of Complex Regional Pain Syndrome
Correspondence: Continuing the “Pain Specialist” Dialogue
Endometriosis and its Misunderstood Etiology
Evolving Management Strategies for Osteoarthritic Pain
Gamma PEMF Therapy: A Pilot Study For Its Use in Managing Opioid Addiction
Guest Editorial: Sex Differences in Pain
How to Provide Effective Pain Management to LGBTQ Individuals
Interscalene Peripheral Nerve Stimulation for Post-Operative Chronic Shoulder Pain
New ICD-11 Codes Set to Improve Pain Care in the Primary Setting
Perspective: Could NGF Antagonists Be the Safest, Most Efficacious Class of Drug We Have to Treat Pain?
Rheumatoid Arthritis and Cognition: Is There a Genetic Link?
Targeting Nerves Provides Alternative to Opioids for Joint Arthroplasty
The Sex Question in Primary and Pain Care
What is capsaicin’s role in treating osteoarthritis?
When Pain Clinicians Have to Be the Villain: Communication Strategies to Bridge the Divide

Can CGRP Help Clarify Why Migraine Is More Common in Women?

An animal study explored how males and females may respond differently to calcitonin gene-related peptide.

With Gregory Dussor, PhD

A leading cause of disability worldwide,1 migraine is two to three times more prevalent among women than men.2,3 Past research has shown us that one major piece of the migraine pathophysiology puzzle is calcitonin gene-related peptide (CGRP), a common and potent vasodilator. While many treatments for migraine work by blocking CGRP activity,4,5 there is still much to learn regarding both the greater female prevalence and how and where CGRP activates the pain fibers associated with migraine.

“The meninges that cover the brain are a fairly important location for headaches,” said Gregory Dussor, PhD, associate professor at the Center for Advanced Pain Studies within the University of Texas at Dallas. “We think that CGRP can, and should, work there.”

Sex differences continue to play a huge role in the presence of pain. (Source: 123RF)

CGRP Exposure and Sex Differences

Dr. Dussor noted a previous paper6 which showed that, when applied to the meninges of rats, CGRPs did not alter pain fibers. He and his team of researchers at the Center for Advanced Pain Studies at the University of Texas at Dallas set out to verify these findings and to challenge the notion that CGRP may trigger migraine pain in the meninges. While the previous study only involved male rats, Dr. Dussor’s team studied rodents of both sexes—a design change that led to an unexpected result.7

“The response to application of CGRP in the meninges of females and males is dramatically different,” said Dr. Dussor. “We got a very robust response in the female and essentially nothing in the male.”

The study involved injecting CGRP into rats (sample sizes ranged from six to 21 across all experiments) as well as mice (sample sizes ranged from four to 12 across all experiments). Behavioral responses were recorded via von Frey testing, a common method that measures withdrawal from tactile stimulation.8 Dr. Dosser explained that von Frey testing allowed his team to assess hypersensitivity in CGRP-injected rodents, with hypersensitivity serving as a proxy for migraine pain.

“It's known that 60 to 80% of migraine patients get this hypersensitivity of their skin during their headaches,” Dr. Dussor said.

Using sets of von Frey filaments—a nylon fishing line-like material that ranges in diameter—Dr. Dussor’s team poked the rodents’ foreheads. They then swapped out thinner filaments for thicker ones in stepwise fashion until each subject withdrew from the contact before enough force could be applied to bend the filament. With this approach, they established a baseline measure of the tactile force required to prompt a withdrawal response. Following injection of CGRP into the meninges, the researchers repeated the procedure on the same individuals to check for changes in facial sensitivity. Echoing the greater prevalence of migraine among women, only the female rodents showed hypersensitivity during von Frey testing after CGRP, withdrawing from significantly reduced tactile force.

Dr. Dussor’s team used an initial dose of 3.8 µg CGRP, which proved insufficient in eliciting a response from males. But, following the positive finding in females, they lowered the dose in 10-fold increments and established that female rats continued to respond with hypersensitivity to a dose of CGRP as low as 1 pg. Testing 1 pg CGRP on mice yielded similar results. In addition, mice and rats together allowed the team to record pain signals spontaneously produced by the animals, namely grimaces.

“Measuring a threshold in response to poking is great, but it's not headache; it's hypersensitivity of the skin,” explained Dr. Dussor. “We can't say with a 100% certainty that the animal is grimacing because it has a headache, but it's another endpoint that is suggestive of headache.”

Using a previously established 3-point scale (no grimace, moderate grimace, and obvious grimace),9 the team then collected grimace scores that ultimately mirrored their hypersensitivity results: only females responded to the CGRP with behaviors indicative of pain.

Primed for Migraine

Further testing revealed that injecting rats with 0.1 ng interleukin-6 (IL-6) primed females to respond to an even smaller dose (0.1 pg) of CGRP. Here, IL-6 also produced tactile hypersensitivity, but the CGRP wasn’t administered until each rat’s behavior returned to baseline. The researchers found similar results by injecting human recombinant brain-derived neurotrophic factor (BDNF) in place of IL-6. Even further testing revealed that CGRP itself primed rats to respond to sodium nitroprusside (SNP) at a dose that does not normally elicit pain.

These experiments may help to explain how a variety of noxious stimuli (CGRP, IL-6, BDNF, SNP) may collectively trigger migraines, with one stimulus priming a pain response to even the slightest exposure of a second stimulus. “You can do something to the animal that clearly causes a response, and it will recover,” said Dr. Dussor. “But there's something about the animal that is different, that now has made it sensitive to all these things that wouldn't normally cause a problem.”

Implications for Treatment

These findings may not lead to any substantial change to migraine pharmacotherapies among human patients. According to Dr. Dussor, the medications currently available for migraine clearly work for both women and men. However, there may be subtle differences between the sexes in terms of how effective the medications are at different doses. For Dr. Dussor, the more important consequence of his study is that CGRP is now implicated in migraine’s greater prevalence among women.

“Why is migraine more common in females? We don't know, and there's probably not one answer, [but] 20 answers,” said Dr. Dussor. “[It] could be that CGRP contributes something very important to the migraine process, and you don't need as much CGRP for that to happen in females as you do males.”

Last updated on: October 7, 2019
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Special Report: CGRP Monoclonal Antibodies for Chronic Migraine
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