@article {Mason2967-16, author = {Bianca N Mason and Eric A Kaiser and Adisa Kuburas and Maria-Cristina M Loomis and John A Latham and Leon F Garcia-Martinez and Andrew F Russo}, title = {Induction of migraine-like photophobic behavior in mice by both peripheral and central CGRP mechanisms}, elocation-id = {2967-16}, year = {2016}, doi = {10.1523/JNEUROSCI.2967-16.2016}, publisher = {Society for Neuroscience}, abstract = {The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. While migraine can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the central nervous system, we used CGRP-induced light aversive behavior in mice as a measure of migraine-associated photophobia. Peripheral (intraperitoneal, IP) injection of CGRP resulted in light aversive behavior in wild-type CD1 mice similar to aversion previously seen following central (intracerebroventricular, ICV) injection. The phenotype was also observed in C57BL/6J mice, although to a lesser degree and with more variability. Following IP CGRP, motility was decreased in the dark only, similar to motility changes following ICV CGRP. In addition, as with ICV CGRP, there was no general increase in anxiety as measured in an open field assay following IP CGRP. Importantly, two clinically effective migraine drugs, the 5-HT1B/D agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after IP CGRP injection, but was seen after ICV CGRP injection. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms and that CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves.SIGNIFICANCE STATEMENTThe neuropeptide CGRP is a central player in migraine pathogenesis, yet its site(s) of action remain unknown. Some preclinical studies have pointed to central sites in the brain and brainstem. However, a peripheral site of action is indicated by the ability of intravenous CGRP to trigger migraine in humans and the efficacy of CGRP receptor antagonists that evidently do no penetrate the CNS in effective amounts. Resolving this issue is particularly important given recent clinical trials showing that anti-CGRP monoclonal antibodies can reduce and even prevent migraine attacks. In this study, we report that CGRP can act in both the brain and the periphery of the mouse to cause migraine-like photophobia by apparently distinct mechanisms.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/early/2016/12/01/JNEUROSCI.2967-16.2016}, eprint = {https://www.jneurosci.org/content/early/2016/12/01/JNEUROSCI.2967-16.2016.full.pdf}, journal = {Journal of Neuroscience} }