Abstract Details

Title Investigating the Roles of the Enzymes MAGL and ABHD6 in Headache Physiology via the KCl Model of Migraine

Topic Headache

Presentation(s) S4 - Hot Topics in Headache Medicine (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

Background Previous work has shown that inhibition of the 2-AG synthesizing enzyme DAGLα produces headache phenotypes in female S/D rats, with corresponding reductions in 2-AG levels within the periaqueductal grey (PAG). Given these findings, it is possible that pathological alterations to the endocannabinoid system may result within other proven animal models of headache.

Objective This study examines the roles of the 2-AG hydrolyzing enzymes MAGL and ABHD6 as they pertain to headache development within the KCl model of migraine. We seek to further our understanding of how modulation of the endocannabinoid system may underlie migraine development.

Design/Methods Headache induction in female S/D rats was performed via application of KCl (0.5uL, 1M) through a dural cannula placed over the V1M cortex, followed by harvest of the PAG at 30 minute timepoints. Tissue underwent LC-MS analysis for 2-AG concentration and western blot analysis for expression of DAGL, MAGL, and ABHD6. In a separate experiment, animals received either MAGL inhibitor (MJN110, 2mg/kg, i.p.) or ABHD6 inhibitor (KT182, 2mg/kg, i.p.) at times pre- and post-KCl administration, followed by von Frey measurement of periorbital withdrawal threshold.

Results Headache induction via dural KCl application resulted in significantly decreased levels of 2-AG within the PAG. Western blot analysis revealed this decrease corresponded with an increase in expression of the 2-AG hydrolyzing enzyme MAGL. Administration of enzyme inhibitors MJN110 and KT182 following dural KCl application significantly reduced KCl induced periorbital allodynia.

Conclusions These results provide evidence of alterations to the 2-AG endocannabinoid system within the PAG during KCl induced headache, aligning with previous data implicating 2-AG in headache development. Inhibition of MAGL and/or ABHD6 may represent a viable route for investigation of preventive and abortive migraine treatments.

Authors/Disclosures
Aidan Levine PRESENTER	Mr. Levine has received research support from University of Arizona MD/PhD Program.
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