Abstract: Breast cancer is the most frequent malignant tumor of women of all races in North America and is the second leading cause of death among women (DHHS, CDC, & NCI; 2014) with an overall NIH estimate costs to the U.S. over $200 billion with $88.7 billion in direct medical costs in 2011. The World Health Organization predicts that global cases of cancer will rise to 15 million new cases by 2020. In advanced stages, skeletal metastasis causes incapacitating pain and is prominent in 75–90% of cancer patients. First line therapy to treat bone cancer pain includes mu opioid receptor agonists. Opioids are well known for producing unwanted side effects in cancer patients including severe somnolence, constipation, etc. but recently have been shown (clinical and preclinical) to enhance the risk of bone loss and fracture. In addition, sustained opioids have demonstrated a propensity for increasing proliferation and migration of different cancers including breast cancer. Data from our laboratory, and others, suggest that cannabinoid CB2 agonists may be effective in alleviating bone cancer pain and bone loss. Selective CB2 agonists significantly inhibit bone cancer pain while NOT resulting in the psychotropic or euphoric effects seen with CB1 agonists or narcotics. Recent reports and data from our lab have identified CB2 agonists as significantly reducing self-administration of drugs of abuse including cocaine and narcotics. Increasing endogenous cannabinoids (MAGL inhibition to increase 2- arachidonylglycerol - 2AG) may regulate bone mass, decrease pro-nociceptive factors and act synergistically with morphine to inhibit cancer-induced bone pain (CIBP) and attenuate tumor proliferation. Our preliminary studies using a murine bone cancer model indicate that MAGL inhibition and CB2 receptor activation inhibits proinflammatory cytokines/chemokines via regulating NF-κB. Yet, there is very little known about the endogenous CB2 system in bone cancer pain/inflammation, and whether the activation of the endocannabinoid (eCB) system, while administering mu opioids, will significantly aid bone cancer patients. There are NO studies investigating the synergistic combination of MAGL inhibitor or CB2 agonists with a mu opioid agonist on cancer pain, bone integrity, tumor proliferation, or attenuating mu opioid unwanted side effects. Our progress in characterizing bone cancer pain has resulted in twelve direct peer-reviewed publications and preliminary data to further support studies of MAGL inhibition, CB2 receptor activation in bone cancer pain. Our preliminary data demonstrate; 1) a reproducible syngeneic breast-induced bone cancer model representative of the clinical state, 2) MAGLipase inhibition resulting in increased 2AG, significantly attenuating cancer-induced pain, 3) exogenous and endogenous CB2 agonists attenuating bone loss, 4) sustained morphine alone increases bone degradation and cytokines, 5) CB2 agonists and MAGL inhibitors decrease NF-kB signal...