TY - JOUR
T1 - Soluble guanylyl cyclase is a critical regulator of migraine-associated pain
AU - Ben Aissa, Manel
AU - Tipton, Alycia F.
AU - Bertels, Zachariah
AU - Gandhi, Ronak
AU - Moye, Laura S.
AU - Novack, Madeline
AU - Bennett, Brian M.
AU - Wang, Yueting
AU - Litosh, Vladislav
AU - Lee, Sue H.
AU - Gaisina, Irina N.
AU - Thatcher, Gregory R.J.
AU - Pradhan, Amynah A.
N1 - Funding Information:
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the NIH-NIDA Grants DA031243 and DA040688, and DoD PR141746 (AAP), and NIH-NCATS UL1TR002003 (GRT). LM and ZB are members of the UIC Graduate Program in Neuroscience.
Publisher Copyright:
© International Headache Society 2017.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Background: Nitric oxide (NO) has been heavily implicated in migraine. Nitroglycerin is a prototypic NO-donor, and triggers migraine in humans. However, nitroglycerin also induces oxidative/nitrosative stress and is a source of peroxynitrite – factors previously linked with migraine etiology. Soluble guanylyl cyclase (sGC) is the high affinity NO receptor in the body, and the aim of this study was to identify the precise role of sGC in acute and chronic migraine. Methods: We developed a novel brain-bioavailable sGC stimulator (VL-102), and tested its hyperalgesic properties in mice. We also determined the effect of VL-102 on c-fos and calcitonin gene related peptide (CGRP) immunoreactivity within the trigeminovascular complex. In addition, we also tested the known sGC inhibitor, ODQ, within the chronic nitroglycerin migraine model. Results: VL-102-evoked acute and chronic mechanical cephalic and hind-paw allodynia in a dose-dependent manner, which was blocked by the migraine medications sumatriptan, propranolol, and topiramate. In addition, VL-102 also increased c-fos and CGRP expressing cells within the trigeminovascular complex. Importantly, ODQ completely inhibited acute and chronic hyperalgesia induced by nitroglycerin. ODQ also blocked hyperalgesia already established by chronic nitroglycerin, implicating this pathway in migraine chronicity. Conclusions: These results indicate that nitroglycerin causes migraine-related pain through stimulation of the sGC pathway, and that super-activation of this receptor may be an important component for the maintenance of chronic migraine. This work opens the possibility for negative sGC modulators as novel migraine therapies.
AB - Background: Nitric oxide (NO) has been heavily implicated in migraine. Nitroglycerin is a prototypic NO-donor, and triggers migraine in humans. However, nitroglycerin also induces oxidative/nitrosative stress and is a source of peroxynitrite – factors previously linked with migraine etiology. Soluble guanylyl cyclase (sGC) is the high affinity NO receptor in the body, and the aim of this study was to identify the precise role of sGC in acute and chronic migraine. Methods: We developed a novel brain-bioavailable sGC stimulator (VL-102), and tested its hyperalgesic properties in mice. We also determined the effect of VL-102 on c-fos and calcitonin gene related peptide (CGRP) immunoreactivity within the trigeminovascular complex. In addition, we also tested the known sGC inhibitor, ODQ, within the chronic nitroglycerin migraine model. Results: VL-102-evoked acute and chronic mechanical cephalic and hind-paw allodynia in a dose-dependent manner, which was blocked by the migraine medications sumatriptan, propranolol, and topiramate. In addition, VL-102 also increased c-fos and CGRP expressing cells within the trigeminovascular complex. Importantly, ODQ completely inhibited acute and chronic hyperalgesia induced by nitroglycerin. ODQ also blocked hyperalgesia already established by chronic nitroglycerin, implicating this pathway in migraine chronicity. Conclusions: These results indicate that nitroglycerin causes migraine-related pain through stimulation of the sGC pathway, and that super-activation of this receptor may be an important component for the maintenance of chronic migraine. This work opens the possibility for negative sGC modulators as novel migraine therapies.
KW - CGRP
KW - Trigeminovascular pain
KW - cGMP
KW - mouse model
KW - nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=85043453610&partnerID=8YFLogxK
U2 - 10.1177/0333102417737778
DO - 10.1177/0333102417737778
M3 - Article
C2 - 29022756
AN - SCOPUS:85043453610
SN - 0333-1024
VL - 38
SP - 1471
EP - 1484
JO - Cephalalgia
JF - Cephalalgia
IS - 8
ER -