Cortical spreading depression (CSD) is a wave of neuronal and glial depolarization followed by suppressed neural activity, thought to underlie migraine aura. While Calcitonin Gene-Related Peptide (CGRP) is well established in migraine pathophysiology, its role in CSD remains uncertain. This comment evaluates evidence suggesting that CGRP is not directly involved in CSD initiation or propagation but may contribute to nociceptive activation associated with migraine. While some studies report CGRP-related effects on CSD susceptibility, methodological limitations raise concerns about their interpretation. Electrophysiological data indicate that CGRP does not influence the ionic mechanisms driving CSD. However, CGRP plays a key role in sensitizing nociceptive neurons, and CGRP-targeting drugs effectively modulate migraine pain without altering CSD dynamics. Clinical findings further suggest that peripheral CGRP inhibition reduces headache burden, potentially allowing the brain to recover from chronic pain states. In conclusion, while CGRP is integral to migraine pain modulation, its direct involvement in CSD appears minimal, highlighting distinct pathways for aura and headache pathophysiology.

OnabotulinumtoxinA (BoNT-A) is an Food and Drug Administration-approved, peripherally acting preventive migraine drug capable of inhibiting meningeal nociceptors. Expanding our view of how else this neurotoxin attenuates the activation of the meningeal nociceptors, we reasoned that if the stimulus that triggers the activation of the nociceptor is lessened, the magnitude and/or duration of the nociceptors' activation could diminish as well. In the current study, we further examine this possibility using electrocorticogram recording techniques, immunohistochemistry, and 2-photon microscopy. We report (1) that scalp (head) but not lumbar (back) injections of BoNT-A shorten the period of profound depression of spontaneous cortical activity that follows a pinprick-induced cortical spreading depression (CSD); (2) that neither scalp nor lumbar injections prevent the induction, occurrence, propagation, or spreading velocity of a single wave of CSD; (3) that cleaved SNAP25—one of the most convincing tools to determine the anatomical targeting of BoNT-A treatment—could easily be detected in pericranial muscles at the injection sites and in nerve fibers of the intracranial dura, but not within any cortical area affected by the CSD; (4) that the absence of cleaved SNAP25 within the cortex and pia is unrelated to whether the blood–brain barrier is intact or compromised; and (5) that BoNT-A does not alter vascular responses to CSD. To the best of our knowledge, this is the first report of peripherally applied BoNT-A's ability to alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine.

Objectives: There has been a long-standing debate over the presence or absence of receptors for botulinum toxin A (BoNT/A) in cephalic areas relevant to migraine pathophysiology and onabotulinumtoxinA (onabotA) sites of action in migraine prevention. To address this issue, we sought to investigate for the first time whether synaptic vesicle protein 2C (SV2C), one member of the SV2 receptor family, is present in axons innervating the dura and periosteum. Methods: Single- and double- labeling immunohistochemical techniques were used to map and characterize the distribution of axons containing SV2C, the third isoform of the SV2 glycoprotein, in the mouse dura and periosteum. Results: Dense networks of axons containing SV2C receptors were distributed throughout all regions of the dura and periosteum. In the dura, SV2C-LIR axons were found in 43% of all peripherin-LIR fibers, 49% of all CGRP-LIR fibers, and 75% of all NaV1.8-LIR fibers. In the periosteum, SV2C-LIR was found in 38% of all peripherin-LIR fibers, 53% of all CGRP-LIR fibers, and 68% of all NaV1.8-LIR fibers. Conclusions: We interpret these findings as suggesting that many of the labeled axons are peripheral nerve axons (peripherin-positive) of unmyelinated sensory and possibly parasympathetic origin (CGRP-positive), and that some of these sensory axons are nociceptors (NaV1.8-positive). Clinically, these findings demonstrate an abundance of axons containing onabotA receptors in the vicinity of scalp structures commonly injected with onabotA for the treatment of chronic migraine. Dense labeling in the periosteum provides another rationale for the possibility that onabotA injections in this layer of the scalp may be advantageous.