Morphine Induced Osteolysis and Hyperalgesia in Models of Traumatic and Pathologic Fracture: Potential for Cannabinoid-Based Therapeutics

Abstract

Pain is the most common reason patients seek out medical attention, although its etiology is different case by case. The over-prescription as well as misuse of opioid therapeutics has created a crisis within the United States that has proven difficult to combat. Metastatic cancer pain as well as orthopedic fracture pain have become some of the largest reasons for the prescription of opioid therapeutics. Despite acute benefits, these drugs possess little long-term efficacy at controlling pain. In addition, there is evidence that chronic opioid use may impair bone healing and worsen osteolysis induced by metastatic cancer spread. To date, there have been few published studies that suggest why these observations may be occurring. Tangentially, there have been studies demonstrating that activation of cannabinoid receptors, especially through cannabinoid receptor 2 (CB2R) activation, by either direct agonism or through modulation of endogenous cannabinoids such as 2-arachidonylglycerol (2-AG) by inhibition of catabolic enzyme monoacylglycerol lipase (MAGL) can promote analgesia in several models. Additionally, studies have demonstrated a dose reduction quality of using CB2 agonists with opioid based therapies for analgesia while helping to alleviate some side effects. While CB2 and Mu opioid agonists have been investigated for many types of pain, it is unknown what effects chronic opioids may have on bone growth and associated bone pain. The purpose of the studies were to investigate the effects of chronic opioids on bone pain and its associated negative metabolic effects, while investigating the therapeutic potential for cannabinoid-based therapies. We determined if the use of a novel MAGL inhibitor, MJN110, had beneficial effects at treating cancer induced bone pain as well as if it had any anti-tumor or pro-osteogenic properties. Next, we investigated a mechanism for the observation of how morphine may be exacerbating osteolysis induced by metastatic cancer spread to the bone via TLR4 activation. Finally, we determined if chronic opioid therapies impaired fracture healing in a model of traumatic fracture and looked to see if CB2 agonism could induce analgesia while not impairing bone healing. Here we show that chronic morphine treatment induces tolerance and hyperalgesia in a murine model of bone cancer, while simultaneously enhancing osteolysis. Additionally, we demonstrate that increasing endogenous cannabinoids by MAGL inhibition maintains efficacy in this bone cancer model, and doesn’t negatively affect bone health. Finally, we show that chronic opioid therapies do not have long term efficacy in a murine model of bone fracture and they delay healing of the fracture, while CB2 agonism maintains analgesic efficacy and does not impair bone healing. This together strongly suggests the further preclinical and clinical investigation of CB2 agonists for the treatment of bone pain.