What Mice Tell Us About the Link Between CGRP and Migraine

Migraine is a recurrent headache disorder that affects approximately 12% (36 million) adults in the United States annually.¹ A migraine attack can last 4 to 72 hours² and is often disabling. Triptans are the most commonly prescribed treatment for migraine, although they help only 40% to 50% of users.³ Triptans, which selectively constrict blood vessels in the brain, were introduced in the 1990s, when dilated vessels were implicated in migraine development.³ 

Advances in neuroimaging disproved the vascular theory of migraine, and the search for alternate causes of migraine led to the neuropeptide calcitonin gene-related peptide (CGRP).

At the 35^th Annual Scientific Meeting of the American Pain Society, Andrew Russo, PhD, Professor, Department of Molecular Physiology and Biophysics, University of Iowa; and Ana Recober, MD, Departments of Neurology and Pediatrics, University of Pennsylvania, Children’s Hospital of Pennsylvania, discussed the role of CGRP in migraine and the clinical implications of their discoveries in mice.

In an interview, Dr Russo said the association between CGRP and migraine came to light 25 years ago, when researchers found that patients had elevated levels of CGRP during a migraine attack, which returned to normal, coincident with headache cessation after administration of serotonin receptor (5HT-1B/1D) agonists, triptans.

Further research into the mechanism of triptans showed they effected headache relief partly by blocking CGRP release from neurons. Olesen and colleagues confirmed the CGRP-migraine link in 2002.⁴ “Olesen’s group reported that injection of CGRP into migraineurs caused delayed migraine-like headaches, while injection into non-migraineurs caused only a mild headache and fullness of head feeling,” Dr Russo said. He explained how those findings prompted him to engineer a mouse model for exploring the CGRP-migraine connection. “I reasoned that migraineurs must be more sensitive to CGRP. From a biochemical perspective, the simplest way to increase sensitivity to CGRP would be if there were more CGRP receptors,” he said. Dr Russo led a series of experiments that showed the “rate-limiting subunit of the CGRP receptor was the RAMP1 protein”. They engineered transgenic mice with elevated RAMP1 in the nervous system.

Detecting migraine in mice proved tricky. Dr Russo said: “we had done studies with migraine patients that showed increased activation of the muscles surrounding the eyes in response to a 1 second flash of light compared with non-migraine subjects. We reasoned that our mice might also show this phenotype.” The eye muscle activation in response to light is referred to as photic-squint, but the researchers found no evidence of photic-squint when the mice were exposed to light. Next, they injected the mice with CGRP. “To our surprise […], injection of CGRP into the mice caused them to squint”, he said. The mice also showed other facial features consistent with pain or discomfort and displayed light aversive behavior. Dr Recober, who has worked closely with Dr Russo, reviewed how their experiments showed that CGRP also induced photophobia in wild-type mice.⁵ Additional research showed that administering a CGRP antagonist or rizatriptan blocked CGRP-induced photophobia in these mice.^[5,6]

Their work implicates photic-squint or photophobia as potential biomarkers for migraine pain, amenable to treatment with CGRP-based therapeutics, and they plan to test the theory in humans. “We are now set up to use facial recognition software to measure the squint response and pain facial features in people when exposed to a flash of light”, Dr Russo said.

Several CGRP-based drugs with various mechanisms are in development. “The CGRP receptor antagonists block CGRP actions at its receptor, the CGRP-blocking antibodies lower the free CGRP levels, and the CGRP receptor-blocking antibodies reduce the number of potential receptors”, Dr Russo explained.  He said in recent phase 2 clinical trials, CGRP-blocking antibodies prevented migraines in about half the participants. Although the findings are promising, Dr Russo cautioned that migraine is a heterogeneous disease, which means CGRP-based treatments are unlikely to work for everyone. “We are hoping that using our model, we can tease out some of the other players that may work with CGRP to contribute to migraine”, Dr Russo said.

References

1. Merikangas KR. Contributions of epidemiology to our understanding of migraine. Headache. 2013;53:230-246.
2. International Headache Society; Headache Classification Committee. The International Classification of Headache Disorders, 3^rd edition (beta version). Cephalagia. 2013;33:629-808.
3. Underwood E. Will antibodies finally put an end to migraines? Science. http://www.sciencemag.org/news/2016/01/feature-will-antibodies-finally-put-end-migraines. January 7, 2016
4. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61.
5. Kaiser EA, Kuburas A, Recober A, Russo AF. Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist. J Neurosci. 2012;32:15439-15449.
6. Recober A, Kuburas A, Zhang Z, Wemmie JA, Anderson MG, Russo AF. Role of calcitonin gene-related peptide in light-aversive behavior: implications for migraine. J Neurosci. 2009;29:8798-8804.