Headache affects more than 39 million Americans, yet a full understanding of the cellular and molecular
pathology underlying headache has not been achieved; the discovery of novel, clinically useful therapeutics is
therefore limited. This proposal will use complimentary techniques to 1) understand the mechanistic
contributions of endocannabinoid system (ECBS) dysregulation to headache pathology and 2) validate a
therapeutic strategy that enhances eCB tone to offer an improved option over current therapeutics. Studies will
use two rat models of headache, cortical spreading depression (CSD) and medication-overuse (MOH) in male
and 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 potential
mechanism of migraine in some patients; however, studies providing evidence for a mechanistic role of eCBs in
migraine are limited. Preliminary data suggest that both cortical KCl and medication overuse deplete 2AG and
increase inflammation in the PAG, a midbrain region implicated in descending pain modulation. Further,
headache symptomology could be induced by pharmacological depletion of 2AG in more female than male rats
further supporting loss of eCB tone in headache in a sex-selective manner. These exciting findings led to the
hypothesis that headache pain results from sex-dependent enhanced degradation of 2AG in the PAG by
ABHD6 and MAGL leading to increased inflammation and loss of descending inhibition that drive pain
behaviors. Three Aims will define the role of ABHD6 as the “gatekeeper” of 2AG availability for retrograde
release (Aim1); determine the role of MAGL in terminating 2-AG actions during headache which may contribute
to maintenance (Aim 2); and establish how ECBS dysregulation within the PAG occurs in males and females at
the 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 in
headache induction and maintenance and validate increasing eCB tone by targeting either MAGL and/or ABHD6
as unique new targets for migraine therapy. Successful completion of this project will provide foundational
rationale to initiate a drug discovery program selectively targeting the ECBS for migraine intervention to provide
a better clinical option against headache as compared to current therapeutics.