RT Journal Article
SR Electronic
T1 The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.262337
DO 10.1124/jpet.119.262337
A1 Thompson, Austen Lowell
A1 Grenald, Shaness
A1 Ciccone, Haley
A1 BassiriRad, Neemah
A1 Niphakis, Micah
A1 Cravatt, Benjamin
A1 Largent-Milnes, Tally Marie
A1 Vanderah, Todd W
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/02/13/jpet.119.262337.abstract
AB Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis are long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer induced bone pain (CIBP). Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activate CB1 and CB2 receptors inhibiting inflammation and pain. We demonstrate that administration of MJN110 significantly and dose-dependently alleviates spontaneous pain behavior during acute administration compared to vehicle control. In addition, the MJN110 maintains its efficacy in a chronic dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose dependent and significant decrease in cell viability of 66.1 breast adenocarcinoma cells and to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden evidenced by radiograph or histological analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer induced bone pain.SIGNIFICANCE STATEMENT Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid based therapies is essential and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.