Sara R. Nass

Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Psychology

Committee Chair

Steven G Kinsey

Committee Co-Chair

Melissa D Blank

Committee Member

Christina L Duncan

Committee Member

Lisa J Robinson

Committee Member

Cole Vonder Haar

Abstract

Rheumatoid arthritis (RA, Table 1) is the most common type of inflammatory arthritis, and is characterized by swelling, inflammation, pain, and destruction of the synovial joints (i.e., knees, elbows, wrists, hips, and fingers). Glucocorticoid receptor agonists are a type of steroid hormone and are among the most common treatments for inflammatory arthritis because of their powerful anti-inflammatory effects. However, harmful side effects are associated with these glucocorticoids (GCs), including increasing patients' vulnerability to infections. Cannabinoids (i.e., cannabis-like signaling molecules) exert anti-inflammatory and analgesic effects with limited side effects compared to traditional immunosuppressants making them excellent targets for the development of new arthritic therapeutics. For example, in mice, selective inhibition of the cannabinoid enzyme monoacylglycerol lipase (MAGL) reduces acute inflammatory pain and edema. Dual administration of drugs are promising novel treatments because it allows lower doses of drugs to attenuate pain and inflammation, while limiting side effects. Combined administration of an endocannabinoid enzyme inhibitor and nonsteroidal anti-inflammatory drug reduces neuropathic and acute pain. Similarly, inflammatory arthritis is reduced by a GC administered with an anti-inflammatory cytokine (i.e., immune system signaling molecule) in mice. Given the anti-inflammatory properties of MAGL inhibition, it is plausible that MAGL inhibition will increase the analgesic and anti-inflammatory effects of a steroid treatment, perhaps reducing the negative side effects of the steroid. Therefore, the goals of the present studies were to determine the analgesic and anti-inflammatory efficacy of (1) the MAGL inhibitor JZL184; (2) the glucocorticoid steroid dexamethasone (DEX); and (3) the combined administration of both JZL184 and DEX. To these ends, we used the collagen-induced arthritis (CIA) mouse model. We found that, although both JZL184 and DEX significantly attenuated proinflammatory cytokine levels in the paws of CIA mice, only DEX decreased pain-related behaviors and paw swelling. Combined administration of a sub-effective dose both drugs was ineffective overall.

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