The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain.

TitleThe Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain.
Publication TypeJournal Article
Year of Publication2020
AuthorsThompson AL, Grenald SA, Ciccone HA, BassiriRad N, Niphakis MJ, Cravatt BF, Largent-Milnes TM, Vanderah TW
JournalJ Pharmacol Exp Ther
Date Published2020 05
KeywordsAnimals, Bone Neoplasms, Cancer Pain, Carbamates, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Endocannabinoids, Female, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Monoacylglycerol Lipases, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Succinimides

Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is 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. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, 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 and proliferation of 66.1 breast adenocarcinoma cells 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, as evidenced by radiograph or histologic 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.

Alternate JournalJ Pharmacol Exp Ther
PubMed ID32054717
PubMed Central IDPMC7160863
Grant ListP01 DA041307 / DA / NIDA NIH HHS / United States
R01 CA142115 / CA / NCI NIH HHS / United States
R01 DA033760 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD
Todd Vanderah, PhD