Date of Graduation
Eberly College of Arts and Sciences
Cole Vonder Haar
Cole Vonder Haar
Cannabinoids have analgesic and anti-inflammatory properties. For example, in preclinical models of acute inflammatory pain, cannabinoid receptor subtype 2 (i.e., CB2, Table 1) agonists decrease paw inflammation and resulting pain. Yet, the anti-inflammatory properties of cannabinoid receptor manipulation in chronic inflammatory pain states are unknown. Monoacylglycerol lipase (MAGL) is the primary catabolic enzyme of the endocannabinoid (i.e., endogenous cannabinoid ligand) 2-arachidonoyl glycerol (i.e., 2-AG). Compounds that inhibit MAGL indirectly increase tissue levels of 2-AG by preventing its catabolism. MAGL inhibitors demonstrate efficacy in acute models of inflammatory/rheumatic disease. Thus, in this study, the MAGL inhibitor JZL184 was tested in a mouse model of inflammatory arthritis. Behavioral, morphological, and immunological signs of collagen-induced arthritis (CIA) were quantified. JZL184 dose-dependently attenuated arthritis-induced paw swelling, per clinical scoring and paw thickness measurement. Consistent with the decreased paw swelling, JZL184 attenuated functional deficits associated with inflammatory arthritis in both a dose- and assay-dependent manner. The selective CB2 antagonist SR144528 was used to determine the necessity of CB2 activation, as an indirect mechanism for MAGL inhibition via JZL184. Paw tissue from mice subjected to CIA showed increased myeloperoxidase levels, indicating neutrophil activation by CIA. While no differences were detected in paw cytokine or chemokine levels, paw cytokines were correlated positively with paw thickness. Thus, MAGL inhibition attenuates behavioral and immune effects of inflammatory arthritis, likely via a mechanism that requires CB2 receptor activation.
Steele, Floyd Franklin III, "Behavioral and Anti-inflammatory Effects of MAGL Inhibition in a Mouse Model of Inflammatory Arthritis" (2019). Graduate Theses, Dissertations, and Problem Reports. 4114.