A large body of evidence supports an important role for calcitonin gene-related 
peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global 
effort to develop a new generation of therapeutics that inhibit the interaction 
of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, 
humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be 
effective in reducing the frequency of migraine. The purpose of this study was 
to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates 
meningeal sensory pathways. To answer this question, we used single-unit 
recording to determine the effects of fremanezumab (30 mg/kg, IV) and its 
isotype control Ab on spontaneous and evoked activity in naive and cortical 
spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal 
trigeminal nucleus of anesthetized male and female rats. The study demonstrates 
that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, 
but not wide-dynamic range trigeminovascular neurons, and that the inhibitory 
effects on the neurons were limited to their activation from the intracranial 
dura but not facial skin or cornea. In addition, when given sufficient time, 
fremanezumab prevents the activation and sensitization of HT neurons by CSD. 
Mechanistically, these findings suggest that HT neurons play a critical role in 
the initiation of the perception of headache and the development of cutaneous 
allodynia and central sensitization. Clinically, the findings may help to 
explain the therapeutic benefit of CGRP-mAb in reducing headaches of 
intracranial origin such as migraine with aura and why this therapeutic approach 
may not be effective for every migraine patient.SIGNIFICANCE STATEMENT 
Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are 
capable of preventing migraine. However, their mechanism of action is unknown. 
In the current study, we show that, if given enough time, a CGRP-mAb can prevent 
the activation and sensitization of high-threshold (central) trigeminovascular 
neurons by cortical spreading depression, but not their activation from the skin 
or cornea, suggesting a potential explanation for selectivity to migraine 
headache, but not other pains, and a predominantly peripheral site of action.