The Roles of the Endogenous Cannabinoid System in Cancer-Induced Bone Pain and Opioid-Induced Reward

Abstract

Chronic pain is a severe problem affecting over 20% of adults worldwide. Opioids, as the current most effective analgesics, are commonly prescribed to manage this devastating symptom. However, the use of opioids is frequently associated with serious side effects, such as respiratory depression and bone degradation. In addition, as opioids possess a profound addiction potential, the wide prescription of opioids has led to a severe opioid epidemic in North American, particularly in the United States. Recently, the endogenous cannabinoid system has emerged as a promising therapeutic target for the treatment of chronic pain and opioid addiction. However, there are still many questions in need of answers before we can translate current research into clinical application. In the present study, we sought to answer two major questions: (1) How can we develop a novel cannabinoid that produces a strong analgesic effect but has limited central side effects? (2) How the endocannabinoid 2-AG and cannabinoid receptor 2 (CB2R) are involved in the chronic opioid-induced reward? Our studies have found that targeting the peripheral CB1Rs can effectively attenuate pain behaviors in a syngeneic murine model of cancer-induced bone pain and results in limited central side effects, as well as other cannabinoid-associated side effects. Furthermore, the elevation of 2-AG tone and activation of CB2Rs remarkedly inhibits chronic morphine-induced reward behavior. Yet, chronic morphine exposure reduces the expression of CB2Rs but does not significantly change the production of 2-AG in the VTA. These data suggest that (1) targeting peripheral CB1Rs can be a valuable therapeutic strategy for treating cancer-induced bone pain, and (2) promoting 2-AG and CB2R signaling may provide therapeutic opportunity for opioid addiction.