The role of endocannabinoid systems on the modulation of migraine

• Applicant: Dr. Chihiro Nozaki, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology ; Pharmacology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 310662498

Previous clinical evidences suggested the contribution of endocannabinoid dysregulation on the etiology and pathophysiology of migraine. Namely, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH), alongside with changes in AEA levels. The precise role of endocannabinoid system on migraine is, however, not clear.We have therefore investigated mice lacking two main cannabinoid receptors CB1 and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), in a nitroglycerin (NTG) -induced migraine model. We found that NTG-induced hyperalgesia and trigeminal neuronal activation were completely abolished in FAAH-deficient mice. Additionally, we found that FAAH inhibitors (URB597 and PF3945) could also dose-dependently block NTG-induced hyperalgesia and the activation of trigeminal neurons. These effects are inhibited by CB1 blocker rimonabant, suggesting that anti-migraine effects of genetic of pharmacological FAAH blockage are mediated by CB1 receptors.It will now be important to elucidate the underlying cellular and molecular mechanisms and to determine exactly how endocannabinoid signaling contributes to the pathophysiology of migraine headaches. In this project, we will address the involvement of FAAH-related endocannabinoid signaling to the experimental model of acute and chronic migraine. I first begin with the evaluation of acute NTG-CGRP evoked facial pain model and medication overuse headache model, in addition to the NTG model that we have used so far. I will adapt these new models to KO mice of FAAH and CB1 receptors, to see if hyperactivation or lack of CB1 receptor mediated signaling also can alter the acute or chronic model of migraine. Then I will study the effect of exogenously applied AEA or a non-hydrolysable AEA derivative on the migraine-like pain and neuronal hyperactivity. This experiment will help us to understand whether AEA is the major endocannabinoid that contributes to the inhibition of acute and chronic migraine. Next, I will investigate whether FAAH activity in blood is important for migraine using bone marrow transplantation. In parallel, topical inhibitor administration will be used to evaluate the role of FAAH on central nervous system.Finally, I will elucidate whether sexual hormones modulate the activity of the endocannabinoid system in a manner that is relevant for the gender difference of migraine-like headache. Ovariectomized female animals will be used to study the contribution of ovarian hormones and endocannabinoid systems on migraine.Overall, this project will address the contribution and major role of the endocannabinoid system on migraine or chronic headache. Present experiments will also clarify the contribution of sexual dimorphism of the endocannabinoid system to the gender difference commonly seen in migraineurs.

• DFG Programme: Research Grants