The University of Arizona
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Targeting the Endocannabinoid System for Headache Intervention

Sponsored by National Institute of Neurological Disorders and Stroke

$1.2M Funding
2 People

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PROJECT SUMMARY Headache affects more than 39 million Americans yet a full understanding of the cellular and molecularpathology underlying headache has not been achieved; the discovery of novel clinically useful therapeutics istherefore limited. This proposal will use complimentary techniques to 1) understand the mechanisticcontributions of endocannabinoid system (ECBS) dysregulation to headache pathology and 2) validate atherapeutic strategy that enhances eCB tone to offer an improved option over current therapeutics. Studies willuse two rat models of headache cortical spreading depression (CSD) and medication-overuse (MOH) in maleand female rats to define the cellular and molecular role played by the ECBS in headache. Recent clinical observations support the idea of Clinical Endocannabinoid Deficiency (CED) as a potentialmechanism of migraine in some patients; however studies providing evidence for a mechanistic role of eCBs inmigraine are limited. Preliminary data suggest that both cortical KCl and medication overuse deplete 2AG andincrease inflammation in the PAG a midbrain region implicated in descending pain modulation. Furtherheadache symptomology could be induced by pharmacological depletion of 2AG in more female than male ratsfurther supporting loss of eCB tone in headache in a sex-selective manner. These exciting findings led to thehypothesis that headache pain results from sex-dependent enhanced degradation of 2AG in the PAG byABHD6 and MAGL leading to increased inflammation and loss of descending inhibition that drive painbehaviors. Three Aims will define the role of ABHD6 as the gatekeeper of 2AG availability for retrograderelease (Aim1); determine the role of MAGL in terminating 2-AG actions during headache which may contributeto maintenance (Aim 2); and establish how ECBS dysregulation within the PAG occurs in males and females atthe molecular and cellular levels during induction maintenance and recovery from headache like pain (Aim 3).Integration of these results between aims will clearly delineate the role of 2-AG within the PAG plays a role inheadache induction and maintenance and validate increasing eCB tone by targeting either MAGL and/or ABHD6as unique new targets for migraine therapy. Successful completion of this project will provide foundationalrationale to initiate a drug discovery program selectively targeting the ECBS for migraine intervention to providea better clinical option against headache as compared to current therapeutics.