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The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain
A L Thompson1, S A Grenald1, H A Ciccone1
1Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona (A.L.T., S.A.G., H.A.C., N.B., T.M.L.-M., T.W.V); Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland (S.A.G.); and The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California (M.J.N., B.F.C.).
Abstract:
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.
Insights
A novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, effectively reduced cancer-induced bone pain in mice. This non-opioid therapeutic shows promise for treating metastatic breast cancer pain without impacting tumor growth.
Area of Science:
- Oncology
- Pain Management
- Pharmacology
Background:
- Metastatic breast cancer frequently affects long bones, causing significant pain.
- Current pain management relies on opioid-based therapies with severe side effects.
- There is a critical need for effective, non-opioid analgesics for cancer pain.
Purpose of the Study:
- To investigate the efficacy of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a mouse model of cancer-induced bone pain.
- To evaluate MJN110's potential as a non-opioid therapeutic for metastatic bone pain.
- To assess MJN110's effects on cancer cell viability and proliferation.
Main Methods:
- Utilized a murine model of cancer-induced bone pain.
- Administered MJN110 acutely and chronically, assessing pain behavior.
- Performed in vitro assays to evaluate MJN110's impact on breast adenocarcinoma cell viability and proliferation.
- Analyzed tumor burden using radiographic and histologic methods.
Main Results:
- MJN110 significantly alleviated spontaneous pain behavior in a dose-dependent manner.
- Chronic administration of MJN110 demonstrated sustained efficacy without receptor sensitization.
- MJN110 reduced breast adenocarcinoma cell viability and proliferation more effectively than other tested agents.
- Tumor burden remained unaffected by chronic MJN110 treatment.
Conclusions:
- MJN110 is a promising therapeutic agent for managing cancer-induced bone pain.
- Targeting MAGL offers a novel, non-opioid strategy for pain relief in metastatic breast cancer.
- MJN110 effectively reduces pain without promoting tumor growth, addressing a significant unmet clinical need.
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