Galcanezumab reduces trigeminal nociception and is effective in preclinical models of migraine and trigeminal autonomic cephalalgias

Marta Vila Pueyo, Kirk W. Johnson, Peter Goadsby, Philip Holland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective:
To assess the therapeutic efficacy of galcanezumab in preclinical models of migraine and cluster headache and to determine potential shared trigeminovascular mechanisms of action.

Background:
Galcanezumab is a humanized monoclonal antibody that binds to the neuropeptide calcitonin gene-related peptide (CGRP) preventing its biological activity. It has been approved as a preventive treatment for both episodic and chronic migraine and episodic cluster headache, the most common trigeminal autonomic cephalalgia.

Methods:
Trigeminovascular and trigeminal-autonomic reflex activation was evoked via electrical stimulation of the dura mater or superior salivatory nucleus (SSN), respectively. Evoked responses were recorded in the spinal trigeminal nucleus along with ongoing spontaneous neuronal and cutaneous noxious and non-noxious-evoked neuronal activity. Rats received either galcanezumab or human control IgG and responses were compared between groups.

Results:
Galcanezumab robustly reduced spontaneous (maximum decrease in dural-evoked: 73% (±3.5) at 4h 30min (P=0.002); in SSN-evoked: 67% (±10.7) at 4h (P=0.01) and cutaneous non-noxious-evoked (maximum decrease in dural-evoked: 50% (±5.7), P=0.004; in SSN-evoked: 47% (±10.5), P=0.005, at the last recording time point) neuronal activation in the trigeminocervical complex, highlighting a general inhibition of trigeminal sensory processing. Further, it significantly inhibited cutaneous noxious (maximum decrease in dural-evoked: 38% (±5.2), P=0.005; in SSN-evoked: 34% (± 7.6), P=0.005, at the last recording time point), durovascular (maximum decrease 48% (±6) at the last recording time point, P=0.001) and SSN-evoked responses (maximum decrease 32% (± 2.6) at 4h, P<0.001), demonstrating a clear reduction of trigeminal nociception, independent of the mode of activation. Galcanezumab did not have any effect on the mean arterial blood pressure.

Conclusion:
Galcanezumab likely acts via a shared trigeminovascular mechanism to dampen noxious and non-noxious sensory stimuli in preclinical models of migraine and trigeminal autonomic cephalalgias. Further supporting the clinical efficacy of galcanezumab for migraine and cluster headache, while demonstrating general inhibition that may be of relevance to other facial pain conditions.
Original languageEnglish
JournalHeadache
Publication statusAccepted/In press - 17 Apr 2025

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