Role of the Endocannabinoid Selective COX-2 Inhibition in Post-Traumatic Headache Associated with Repetitive Mild Traumatic Brain Injury
Abstract
Posttraumatic headache (PTH) is one of the most common and debilitating sequelae attributed to traumatic brain injury (TBI). Ina substantial number of patients, PTH can become persistent and significantly impair the patients quality of life. Most TBI cases exhibit migraine and tension type headache phenotypes, suggesting that PTH may share some common pathophysiology with the primary headache disorders. Although modulation of the endocannabinoid system suppresses various types of pain that include migraine and studies from us and others point to its therapeutic potential in the TBI animal models, the role of endocannabinoids in the treatment of PTH has not been explored. Using our recently developed PTH mouse model induced by closed-head impact model of engineered rotational acceleration (CHIMERA), we found that pharmacological inhibition and genetic deletion of monoacylglycerol lipase (MAGL) that degrades the endocannabinoid 2-arachidonoyl glycerol (2-AG) reduced neuroinflammation, calcitonin gene related peptide (CGRP) production and periorbital allodynia, whereas inhibition or deletion of the anandamide (AEA) hydrolytic enzyme, fatty acid amide hydrolase (FAAH) failed to reduce headache and even exacerbated inflammatory response in the trigeminal system. Interestingly, periorbital allodynia in the FAAH knockout mice following repetitive mild TBI (mTBI) is alleviated by inhibition of the transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel mediating pain initiation and progression. Consistently, arachidonoyl serotonin (AA-5-HT), a dual inhibitor of FAAH and TRPV1almost completely alleviated TBI-induced inflammatory response and nociception in the FAAH wild type mice. These results suggest that blockade of TRPV1 activity is able to enhance the antinociceptive effect of the endogenous AEA.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1214660
Entities
People
- Yumin Zhang
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine