Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in 
primary afferent sensory neurons, is strongly implicated in the pathophysiology 
of migraine headache, but its role in migraine is still equivocal. As a new 
approach to migraine treatment, humanized anti-CGRP monoclonal antibodies 
(CGRP-mAbs) were developed to reduce the availability of CGRP, and were found 
effective in reducing the frequency of chronic and episodic migraine. We 
recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the 
activity of second-order trigeminovascular dorsal horn neurons that receive 
peripheral input from the cranial dura, and found a selective inhibition of 
high-threshold but not wide-dynamic range class of neurons. To investigate the 
basis for this selective inhibitory effect, and further explore the mechanism of 
action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical 
spreading depression-evoked activation of mechanosensitive primary afferent 
meningeal nociceptors that innervate the cranial dura, using single-unit 
recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab 
pretreatment selectively inhibited the responsiveness of Aδ neurons, but not 
C-fiber neurons, as reflected in a decrease in the percentage of neurons that 
showed activation by cortical spreading depression. These findings identify Aδ 
meningeal nociceptors as a likely site of action of fremanezumab in the 
prevention of headache. The selectivity in its peripheral inhibitory action may 
partly account for fremanezumab's selective inhibition of high-threshold, as a 
result of a predominant A-δ input to high-threshold neurons, but not wide 
dynamic-range dorsal horn neurons, and why it may not be effective in all 
migraine patients.SIGNIFICANCE STATEMENT Recently, we reported that humanized 
CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of 
high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by 
cortical spreading depression (CSD). In the current paper, we report that 
CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by 
CSD. This is the first identification of an anti-migraine drug that appears to 
be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the 
main CGRP-mAb site of action appears to be situated outside the brain, we 
conclude that the initiation of the headache phase of migraine depends on 
activation of meningeal nociceptors, and that for selected patients, activation 
of the Aδ-HT pain pathway may be sufficient for the generation of headache 
perception.