The Role of the Recently Deorphanized G-Protein Coupled Receptor, GPR171, in Morphine Tolerance and Withdrawal

Opioid analgesics, such as morphine, represent the gold standard pain killer and the most frequently used drugs for the treatment of moderate to severe pain. Despite being a potent analgesic, morphine has unwanted and dangerous side effects with repeated use, such as tolerance and withdrawal. Tolerance is a state when a person no longer responds to a drug and a higher dose is required to achieve the same initial pain relief. Withdrawal is a set of undesirable psychological and physiological symptoms that occur after someone stops taking a drug or reduces the dose. Morphine tolerance and withdrawal play a vital role in the development of opioid addiction. One of the crucial goals to reduce opioid addiction is to develop pain therapeutics for chronic pain with high efficacy and reduced side effects. Despite centuries of extensive research, the existing treatments for chronic pain have met with limited success and developing better and alternative therapies are urgently needed. A novel G-protein coupled receptor, GPR171, is found to be highly expressed throughout the pain modulating regions of the brain. Our previous study found that activating this receptor with an agonist, enhances morphine’s pain relieving property in combination therapy during acute treatment in mice. In this study, we investigated the effects of activating this receptor during long-term morphine treatment to evaluate tolerance and withdrawal. Our results demonstrate that, activating this receptor reduces morphine induced tolerance in female mice (but not males) on a thermal pain test and it does not have any additional adverse effects on morphine tolerance and withdrawal syndrome. These results suggest the potentiality of GPR171 as a novel pain therapeutics in combination with morphine with enhanced efficacy and reduced tolerance and dependence for the treatment of chronic pain, especially for females