Research Summary

CGRP Activates Migraine-Related Meningeal Nociceptive Pathways

Edited by:
Ashton L. Stahl

Key Highlights

  • Intra-carotid CGRP activated 59% of first-order and 75% of second-order neurons.
  • CGRP sensitized 63% of first-order and 70% of second-order neurons to dural stimulation.
  • Early local anesthetic blockade prevented CGRP-induced activation, whereas delayed blockade did not.
  • No significant sex differences were observed in baseline activity or CGRP-induced responses.

Intra-carotid calcitonin gene-related peptide (CGRP) activated and sensitized peripheral and central neurons in the meningeal sensory pathway of anesthetized rats, according to a study published in Brain. The findings identify the dura as a critical site of CGRP action in initiating migraine-related nociceptive signaling.

Researchers performed single-unit recordings in male and female Sprague-Dawley rats to assess CGRP's effects on first-order neurons in the trigeminal ganglion and second-order neurons in the upper cervical dorsal horn. CGRP was delivered by intra-carotid infusion for 20 minutes, and neuronal activation and sensitization were measured through spontaneous firing and responses to mechanical stimulation of dural and facial receptive fields. The investigators also applied local anesthetic to the dura or trigeminal ganglion at different time points to assess the contribution of peripheral input.

Editor’s note: The article reports inconsistent intra-carotid CGRP doses: 50 ng/kg/min in the Methods section and Figure 1 and 5 μg/kg/min in the abstract and Results section.

Study Findings

Intra-carotid CGRP increased firing in 19 of 32 first-order neurons (59%), including 10 of 16 Aδ fibers and 9 of 16 C fibers. It also activated 18 of 24 second-order neurons (75%), comprising 9 of 12 high-threshold neurons and 9 of 12 wide-dynamic-range neurons. Saline activated none of the tested first- or second-order neurons. Activation began earlier in Aδ fibers than in C fibers, with median latencies of 17.5 and 90 minutes, respectively (P = .0005).

CGRP enhanced responses to dural stimulation in 12 of 19 first-order neurons (63%) and 17 of 24 second-order neurons (70%). Trigeminal ganglion injection of CGRP activated 8 of 9 second-order neurons, and all 9 were sensitized to dural and facial stimulation. Applying lidocaine to the dura before CGRP infusion prevented activation and sensitization in all tested first- and second-order neurons. Trigeminal ganglion blockade within the first hour inhibited activation, but blockade at later time points did not. No significant sex differences were found in baseline neuronal activity or in the magnitude and timing of CGRP-induced responses.

Clinical Implications

According to the study authors, the findings suggest that CGRP initiates migraine-related nociceptive signaling through peripheral action, particularly at the dura, before central sensitization becomes independent of continuing peripheral input. The authors stated that this early window supports the therapeutic rationale for early administration of peripherally acting CGRP-targeted treatments during acute migraine attacks.

The authors also said the results provide a mechanistic explanation for the clinical efficacy of peripherally acting CGRP antagonists and monoclonal antibodies.

Expert Commentary

“Intra-carotid—but not systemic—administration of CGRP activates and sensitizes first- and second-order neurons of the meningeal sensory pathway in rats,” the researchers concluded.

Reference

Melo-Carrillo A, Strassman AM, Burstein R. Elucidating the nociceptive role of CGRP in migraine headache. Brain. 2026;149(8):2760-2773. doi:10.1093/brain/awag008