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Abstract
Morphine has a potency and efficacy for producing analgesia and a pharmacokinetic profile that make it favorable for use in pain treatment. Continued use of morphine and other opioids results in some degree of tolerance, such that the dose needs to be escalated to achieve the same effect. This can become problematic in the treatment of chronic pain, as elevated doses of opioids can produce unwanted side effects such as respiratory depression and dependence. Methadone, a synthetic agonist, is being increasingly used in the treatment of pain. In cancer patients, less dose escalation is required for those who are receiving sustained release methadone versus morphine. Thus the development of tolerance may differ depending on the agonist being used and understanding the adaptations that produce tolerance will be useful for pain treatment. The goal of this work is to understand the cellular mechanisms involved in desensitization and resensitization of mu opioid receptors in the locus coeruleus (LC) and how these processes are regulated by acute and long‐term administration of various opioids. To do this electrophysiological recording was used to measure mu opioid receptor (MOR) stimulated hyperpolarizations and 2‐photon imaging of epitope‐tagged receptors was used to monitor MOR trafficking in neurons in live brain slices. Desensitization and internalization induced by various agonists was examined in opiate naïve LC neurons. [Met5]‐enkephalin, methadone and etorphine resulted in both desensitization and internalization while oxycodone caused neither. Morphine