@article {Zhao151464, author = {Jun Zhao and Dan Levy}, title = {CGRP signaling mediates prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization}, elocation-id = {151464}, year = {2017}, doi = {10.1101/151464}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Cortical spreading depression (CSD) is believed to promote migraine headache by enhancing the activity and mechanosensitivity of trigeminal intracranial meningeal afferents. One putative mechanism underlying this afferent response involves an acute excitation of meningeal afferents by cortical efflux of K+ and the ensuing antidromic release of pro-inflammatory sensory neuropeptides, such as calcitonin gene-related peptide (CGRP). We employed extracellular single-unit recording in anesthetized rats to determine whether a brief K+ stimulus could lead to CGRP-dependent enhancement of meningeal afferent responses. In addition, we tested if CSD-evoked meningeal afferent responses involve CGRP signaling. Acute meningeal K+ stimulation promoted a 2.3{\textpm}0.4 fold increase in the ongoing activity level of ~65\% of the afferents tested. Neural activation developed following a 23.3{\textpm}4.1min delay and lasted for 22.2{\textpm}5.6min. Meningeal afferent mechanosensitivity was not altered by the K+ stimulation. Pretreatment with the CGRP receptor inhibitor BIBN4096 (333μM, i.v.) suppressed the K+-related prolonged afferent activation but had no effect on the prolonged increase in ongoing activity and mechanosensitivity of meningeal afferents evoked by CSD. While CGRP-mediated activation of meningeal afferents evoked by cortical efflux of excitatory mediators could promote headache, this mechanism is unlikely to play a key role in mediating the headache of migraine triggered by CSD.}, URL = {https://www.biorxiv.org/content/early/2017/06/17/151464}, eprint = {https://www.biorxiv.org/content/early/2017/06/17/151464.full.pdf}, journal = {bioRxiv} }