Summary: CGRP, a protein associated with migraine pain, appears to act differently between sexes. Researchers say a female-specific mechanism of downstream CGRP receptor activation is likely to contribute to the higher prevalence of migraine in women.
Source: UT Dallas
A new preclinical study from University of Texas at Dallas researchers may help explain why migraine is three times more common in women than men.
In research published online April 8 in the Journal of Neuroscience, a protein implicated in the development of migraine symptoms caused pain responses in female rodents, but not in males, when introduced into the meninges, the protective tissue layers surrounding the brain.
Most previous preclinical investigations of migraine and the protein, called calcitonin gene-related peptide (CGRP), used only male animals, leaving the question of neurobiological sex differences unanswered, said Dr. Greg Dussor, the corresponding author of the study and an associate professor of neuroscience in the UT Dallas School of Behavioral and Brain Sciences.
“This is the first study to show that CGRP might act differently between sexes,” said Dussor, Fellow, Eugene McDermott Professor. “It also shows that CGRP can have a pain-related effect in the meninges, which is something that has been questioned in the literature previously.”
Migraine — a condition defined by severe periodic headaches often accompanied by nausea, vision disturbances and light or sound sensitivity — is the most common neurological disorder worldwide and the second-leading cause of disability. Despite CGRP’s well-established role in migraine, it is unknown where in the body it contributes to the condition.
“We already know CGRP has a prominent role in migraine. It’s been investigated for more than 30 years,” Dussor said. “CGRP is produced both in the central nervous system — the brain and spinal cord — and in the peripheral nervous system, which goes everywhere else, including the meninges. But it can’t move between the two; it’s too large to cross the blood-brain barrier that shields the central nervous system.”
The neurons that innervate the meninges signal the pain of a headache. However, because of the full range of symptoms and phases involved in migraine, the condition is believed to start in the brain.
The experiment involved injecting small doses of CGRP into the dura mater, the outermost layer of the meninges. Only female animals experienced headache symptoms. The researchers observed a similar pain response in the female animals’ paws when injected there.
“That response shows that females may be more sensitive to CGRP throughout the body, not just the meninges,” Dussor said. “But we don’t know what that means for other types of pain yet.”
The reasons for migraine’s prevalence in females are likely complex. Because the male rodents were unaffected by introducing CGRP into the meninges, Dussor said the study does suggest that CGRP-based signaling from the meninges may contribute to the female-biased nature of this disorder.
In the wake of CGRP gaining more attention in migraine prevention research, the Food and Drug Administration has recently approved three therapeutic drugs that block the protein.
“Although CGRP plays a clear role in migraine, this does not imply that migraine is exclusively a CGRP-based disorder,” Dussor said. “This is just the beginning of demonstrations showing that CGRP might act differently in women.”
Funding: The study was funded by the National Institutes of Health. Additional authors from UT Dallas include Dr. Ted Price BS’97, Eugene McDermott Professor of neuroscience; Dr. Michael Burton, assistant professor in the School of Behavioral and Brain Sciences; Dr. Carolina Burgos-Vega, a research assistant who earned her PhD from UT Dallas in 2017; and Amanda Avona MS’18, a doctoral student in neuroscience. Dr. Armen Akopian, associate professor of endodontics at The University of Texas Health Science Center at San Antonio, also contributed to the research.
Migraine is the second leading cause for disability worldwide and the most common neurological disorder. It is also three times more common in women; reasons for this sex difference are not known. Using preclinical behavioral models of migraine, we show that application of CGRP to the rat dura mater produces cutaneous periorbital hypersensitivity. Surprisingly, this response was observed only in females; dural CGRP at doses from 1 pg to 3.8 μg produce no responses in males. In females, dural CGRP causes priming to a pH 7.0 solution after animals recover from the initial CGRP-induced allodynia. Dural application of interleukin-6 (IL-6) causes acute responses in males and females but only causes priming to subthreshold dural CGRP (0.1 pg) in females. Intracisternal application of BDNF also causes similar acute hypersensitivity responses in males and females but only priming to subthreshold dural CGRP (0.1 pg) in females. Females were additionally primed to a subthreshold dose of the NO-donor sodium nitroprusside (0.1 mg/kg) following dural CGRP. Finally, the sexually-dimorphic responses to dural CGRP were not specific to rats as similar female-specific hypersensitivity responses were seen in mice, where increased grimace responses were also observed. These data are the first to demonstrate that CGRP induced headache-like behavioral responses at doses up to 3.8 μg are female specific both acutely and following central and peripheral priming. These data further implicate dural CGRP signaling in the pathophysiology of migraine and propose a model where dural CGRP-based mechanisms contribute to the sexual disparity of this female biased disorder.
STATEMENT OF SIGNIFICANCE:
Calcitonin gene-related peptide has long been implicated in the pathophysiology of migraine and CGRP-based therapeutics are efficacious for the treatment of migraine in humans. However, the location of action for CGRP in migraine remains unclear. We show here that application of CGRP to the cranial meninges causes behavioral responses consistent with headache in preclinical rodent models. Surprisingly however, these responses are only observed in females. Acute responses to meningeal CGRP are female-specific and sensitization to CGRP after two-distinct stimuli are also female-specific. These data implicate the dura mater as a primary location of action for CGRP in migraine and suggest that female-specific mechanisms downstream of CGRP receptor activation contribute to the higher prevalence of migraine in women.