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DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache

Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the p...

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Autores principales: Levine, Aidan, Liktor-Busa, Erika, Karlage, Kelly L., Giancotti, Luigi, Salvemini, Daniela, Vanderah, Todd W., Largent-Milnes, Tally M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874129/
https://www.ncbi.nlm.nih.gov/pubmed/33584293
http://dx.doi.org/10.3389/fphar.2020.615028
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author Levine, Aidan
Liktor-Busa, Erika
Karlage, Kelly L.
Giancotti, Luigi
Salvemini, Daniela
Vanderah, Todd W.
Largent-Milnes, Tally M.
author_facet Levine, Aidan
Liktor-Busa, Erika
Karlage, Kelly L.
Giancotti, Luigi
Salvemini, Daniela
Vanderah, Todd W.
Largent-Milnes, Tally M.
author_sort Levine, Aidan
collection PubMed
description Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the periaqueductal gray (PAG) and anandamide (AEA) increased in the cortex suggesting distinct regulation of the endocannabinoid system during headache pain. These results led to the hypothesis that blockade of DAGL, to reduce 2-AG levels would induce headache-like behaviors as a new, translationally relevant model of episodic headache. Our study investigated whether non-selective and selective blockade of DAGL, the main biosynthetic enzyme for 2-AG, induced periorbital and hind-paw allodynia, photophobia, anxiety-like behaviors, responsivity to abortive anti-migraine agents, and 2-AG/AEA levels. Injection of non-selective DAGL (DH376, 10 mg/kg, IP) and selective DAGLα (LEI106, 20 mg/kg, IP) inhibitors, but not DAGLβ agents, induced facial sensitivity in 100% and ∼60% of female and male rats, respectively, without induction of peripheral sensitivity. Notably, male rats showed significantly less sensitivity than female rats after DAGLα inhibition, suggesting sexual dimorphism in this mechanism. Importantly, LEI106 induced periorbital allodynia was attenuated by administration of the clinically available abortive antimigraine agents, sumatriptan and olcegepant. Selective DAGLα inhibition induced significant photophobia as measured by the light-dark box, without anxiety like behaviors or changes in voluntary movement. Analysis of AEA and 2-AG levels at the time of peak pain sensitivity revealed reductions in 2-AG in the visual cortex and periaqueductal gray (PAG), without altering anandamide or significantly increasing diacylglycerol levels. These results provide foundational evidence for DAGL-2AG in the induction of headache-like pain and photophobia without extracephalic allodynia, thus modeling the clinical episodic migraine. Mechanistically, behavioral measures of headache sensitivity after DAGL inhibition suggests that reduced 2-AG signaling in the cortex and PAG, but not the trigeminal nucleus caudalis or trigeminal ganglia, drives headache initiation. Therefore, episodic DAGL inhibition, which reduces the time, cost, and invasiveness of currently accepted models of headache, may fill the need for episodic migraine/headache models mirroring clinical presentation. Moreover, use of this approach may provide an avenue to study the transition from episodic to chronic headache.
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spelling pubmed-78741292021-02-11 DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache Levine, Aidan Liktor-Busa, Erika Karlage, Kelly L. Giancotti, Luigi Salvemini, Daniela Vanderah, Todd W. Largent-Milnes, Tally M. Front Pharmacol Pharmacology Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the periaqueductal gray (PAG) and anandamide (AEA) increased in the cortex suggesting distinct regulation of the endocannabinoid system during headache pain. These results led to the hypothesis that blockade of DAGL, to reduce 2-AG levels would induce headache-like behaviors as a new, translationally relevant model of episodic headache. Our study investigated whether non-selective and selective blockade of DAGL, the main biosynthetic enzyme for 2-AG, induced periorbital and hind-paw allodynia, photophobia, anxiety-like behaviors, responsivity to abortive anti-migraine agents, and 2-AG/AEA levels. Injection of non-selective DAGL (DH376, 10 mg/kg, IP) and selective DAGLα (LEI106, 20 mg/kg, IP) inhibitors, but not DAGLβ agents, induced facial sensitivity in 100% and ∼60% of female and male rats, respectively, without induction of peripheral sensitivity. Notably, male rats showed significantly less sensitivity than female rats after DAGLα inhibition, suggesting sexual dimorphism in this mechanism. Importantly, LEI106 induced periorbital allodynia was attenuated by administration of the clinically available abortive antimigraine agents, sumatriptan and olcegepant. Selective DAGLα inhibition induced significant photophobia as measured by the light-dark box, without anxiety like behaviors or changes in voluntary movement. Analysis of AEA and 2-AG levels at the time of peak pain sensitivity revealed reductions in 2-AG in the visual cortex and periaqueductal gray (PAG), without altering anandamide or significantly increasing diacylglycerol levels. These results provide foundational evidence for DAGL-2AG in the induction of headache-like pain and photophobia without extracephalic allodynia, thus modeling the clinical episodic migraine. Mechanistically, behavioral measures of headache sensitivity after DAGL inhibition suggests that reduced 2-AG signaling in the cortex and PAG, but not the trigeminal nucleus caudalis or trigeminal ganglia, drives headache initiation. Therefore, episodic DAGL inhibition, which reduces the time, cost, and invasiveness of currently accepted models of headache, may fill the need for episodic migraine/headache models mirroring clinical presentation. Moreover, use of this approach may provide an avenue to study the transition from episodic to chronic headache. Frontiers Media S.A. 2021-01-12 /pmc/articles/PMC7874129/ /pubmed/33584293 http://dx.doi.org/10.3389/fphar.2020.615028 Text en Copyright © 2021 Levine, Liktor-Busa, Karlage, Giancotti, Salvemini, Vanderah and Largent-Milnes. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Levine, Aidan
Liktor-Busa, Erika
Karlage, Kelly L.
Giancotti, Luigi
Salvemini, Daniela
Vanderah, Todd W.
Largent-Milnes, Tally M.
DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title_full DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title_fullStr DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title_full_unstemmed DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title_short DAGLα Inhibition as a Non-invasive and Translational Model of Episodic Headache
title_sort daglα inhibition as a non-invasive and translational model of episodic headache
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874129/
https://www.ncbi.nlm.nih.gov/pubmed/33584293
http://dx.doi.org/10.3389/fphar.2020.615028
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