Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update

Drug addiction is a global health problem and continues to place an enormous financial burden on society. This addiction is characterized by drug dependence sensitization and craving. Morphine has been widely used for pain relief, but chronic administration of morphine causes analgesic tolerance, hyperalgesia, and addiction, all of which limit its clinical usage. Alterations of multiple molecular pathways have been reported to be involved in the development of drug addiction, including mitochondrial dysfunction, excessive oxidative stress and nitric oxide stress, and increased levels of apoptosis, autophagy, and neuroinflammation. Preclinical and clinical studies have shown that the co-administration of melatonin with morphine leads to a reversal of these affected pathways. In addition, murine models have shown that melatonin improves morphine-induced analgesic tolerance and addictive behaviors, such as behavioral sensitization, reward effect, and physical dependence. In this review, we attempt to summarize the recent findings about the beneficial effect and molecular mechanism of melatonin on mitochondrial dysfunction, uncontrolled autophagy, and neuroinflammation in morphine addiction and morphine analgesic tolerance. We propose that melatonin might be a useful supplement in the treatment opiate abuse.