@article{89ccd77fceea4de88670274c84d00952,
title = "ABHD6 and MAGL control 2-AG levels in the PAG and allodynia in a CSD-induced periorbital model of headache",
abstract = "Introduction: The high prevalence and severe symptoms of migraines in humans emphasizes the need to identify underlying mechanisms that can be targeted for therapeutic benefit. Clinical Endocannabinoid Deficiency (CED) posits that reduced endocannabinoid tone may contribute to migraine development and other neuropathic pain conditions. While strategies that increase levels of the endocannabinoid n-arachidonoylethanolamide have been tested, few studies have investigated targeting the levels of the more abundant endocannabinoid, 2-arachidonoylgycerol, as an effective migraine intervention. Methods: Cortical spreading depression was induced in female Sprague Dawley rats via KCl (potassium chloride) administration, followed by measures of endocannabinoid levels, enzyme activity, and neuroinflammatory markers. Efficacy of inhibiting 2-arachidonoylglycerol hydrolysis to mitigate periorbital allodynia was then tested using reversal and prevention paradigms. Results: We discovered reduced 2-arachidonoylglycerol levels in the periaqueductal grey associated with increased hydrolysis following headache induction. Pharmacological inhibition of the 2-arachidonoylglycerol hydrolyzing enzymes, α/β-hydrolase domain-containing 6 and monoacylglycerol lipase reversed and prevented induced periorbital allodynia in a cannabinoid receptor-dependent manner. Discussion: Our study unravels a mechanistic link between 2-arachidonoylglycerol hydrolysis activity in the periaqueductal grey in a preclinical, rat model of migraine. Thus, 2-arachidonoylglycerol hydrolysis inhibitors represent a potential new therapeutic avenue for the treatment of headache.",
keywords = "2-AG, ABHD6, MAGL, PAG, endocannabinoid, migraine",
author = "Erika Liktor-Busa and Levine, {Aidan A.} and Palomino, {Seph M.} and Simar Singh and Jared Wahl and Vanderah, {Todd W.} and Nephi Stella and Largent-Milnes, {Tally M.}",
note = "Funding Information: This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS099292 and R01NS126752-01A1 to TML and R21NS118130 to NS) and the National Institute of Drug Abuse (DA047626 to NS) of the National Institutes of Health; Arizona Biomedical Research Commission (ABRC45952, TML), with monies from the Department of Pharmacology at the University of Arizona, the M.D.-Ph.D. Program at the University of Arizona, the University of Arizona Comprehensive Pain and Addiction Center, and the NIDA Center for Excellence in Addiction Studies (P30DA051355). Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA023074. Authors are solely responsible for the content which does not necessarily represent the official views of the National Institutes of Health, the State of Arizona, or the University of Arizona. Acknowledgments Funding Information: This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS099292 and R01NS126752-01A1 to TML and R21NS118130 to NS) and the National Institute of Drug Abuse (DA047626 to NS) of the National Institutes of Health; Arizona Biomedical Research Commission (ABRC45952, TML), with monies from the Department of Pharmacology at the University of Arizona, the M.D.-Ph.D. Program at the University of Arizona, the University of Arizona Comprehensive Pain and Addiction Center, and the NIDA Center for Excellence in Addiction Studies (P30DA051355). Research reported in this publication was also supported by the National Cancer Institute of the National Institutes of Health under award number P30CA023074. Authors are solely responsible for the content which does not necessarily represent the official views of the National Institutes of Health, the State of Arizona, or the University of Arizona. Publisher Copyright: 2023 Liktor-Busa, Levine, Palomino, Singh, Wahl, Vanderah, Stella and Largent-Milnes.",
year = "2023",
doi = "10.3389/fpain.2023.1171188",
language = "English (US)",
volume = "4",
journal = "Frontiers in Pain Research",
issn = "2673-561X",
publisher = "Frontiers Media S. A.",
}