Back to Search
Start Over
Inhibition of 2-AG hydrolysis alleviates posttraumatic headache attributed to mild traumatic brain injury.
- Source :
-
The journal of headache and pain [J Headache Pain] 2024 Jul 16; Vol. 25 (1), pp. 115. Date of Electronic Publication: 2024 Jul 16. - Publication Year :
- 2024
-
Abstract
- Background: Posttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated.<br />Methods: Repetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the "Up-Down" method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed.<br />Results: The rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively.<br />Conclusion: Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation.<br /> (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Subjects :
- Animals
Male
Mice
Disease Models, Animal
Hyperalgesia drug therapy
Hyperalgesia etiology
Hydrolysis
Calcitonin Gene-Related Peptide metabolism
Trigeminal Ganglion metabolism
Trigeminal Ganglion drug effects
Piperidines pharmacology
Piperidines therapeutic use
Polyunsaturated Alkamides pharmacology
Endocannabinoids metabolism
Brain Concussion complications
Brain Concussion drug therapy
Arachidonic Acids pharmacology
Mice, Inbred C57BL
Post-Traumatic Headache etiology
Post-Traumatic Headache drug therapy
Glycerides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1129-2377
- Volume :
- 25
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The journal of headache and pain
- Publication Type :
- Academic Journal
- Accession number :
- 39014318
- Full Text :
- https://doi.org/10.1186/s10194-024-01817-z