How does Calcitonin Gene-Related Peptide (CGRP) cause headaches?

From the Guidelines

CGRP causes headaches by triggering inflammation and vasodilation in the brain's blood vessels, a process that is effectively targeted by CGRP receptor antagonists and CGRP monoclonal antibodies, as supported by recent evidence from the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline for the management of headache 1.

Mechanism of CGRP in Headaches

• CGRP is released from trigeminal nerve endings and binds to receptors on blood vessels, causing them to widen and become leaky.
• This dilation creates pressure and allows inflammatory substances to escape into surrounding tissues, activating pain pathways.
• CGRP also directly sensitizes pain receptors, making them more responsive to stimuli that wouldn't normally cause pain.
• Additionally, CGRP promotes neurogenic inflammation by stimulating the release of other inflammatory substances, creating a cascade effect that amplifies pain signals.

Treatment Implications

• CGRP receptor antagonists (like rimegepant, ubrogepant) and CGRP monoclonal antibodies (such as erenumab, fremanezumab, galcanezumab, and eptinezumab) are effective migraine treatments.
• These medications work by either blocking CGRP from binding to its receptors or by neutralizing CGRP molecules directly, preventing the inflammatory cascade that leads to headache pain.
• The 2023 guideline provides a "strong for" recommendation for the use of erenumab, fremanezumab, and galcanezumab for the prevention of episodic migraine (EM) or chronic migraine (CM) 1.
• Gepants, such as atogepant and rimegepant, have also been recommended for the acute treatment of migraine, with atogepant receiving a "weak for" recommendation for EM prevention 1.

From the Research

CGRP and Headaches

• CGRP (calcitonin gene-related peptide) is a neuropeptide that plays a crucial role in migraine pathophysiology 2, 3.
• CGRP is expressed in and released from a subset of polymodal primary sensory neurons of the trigeminal ganglion, and its release in the dorsal spinal cord has been associated with nociceptive transmission 2.
• CGRP levels increase in the cranial circulation during migraine attacks, and CGRP injection in migraineurs results in migraine-like attacks 2.
• The exact mechanism by which CGRP causes headaches is not fully understood, but it is thought to involve the dilation of blood vessels and the transmission of pain signals 2, 3.

CGRP Receptors and Pain Transmission

• CGRP receptors are found in the trigeminal ganglion and are involved in the transmission of pain signals 2.
• The activation of CGRP receptors leads to the release of pain-producing chemicals, such as substance P and neurokinin A 2.
• CGRP receptor antagonists, such as olcegepant and telcagepant, have been shown to be effective in the treatment of migraine attacks, suggesting that CGRP plays a key role in migraine pathophysiology 2.

Therapeutic Targeting of CGRP

• CGRP-targeting drugs, such as monoclonal antibodies, have been developed and have shown efficacy in the treatment of migraine 3.
• These drugs work by blocking the action of CGRP, thereby reducing the transmission of pain signals and the dilation of blood vessels 3.
• The safety profile of CGRP-targeting drugs is generally good, with few side effects reported 3, 4.