Changes in µ-opioid receptor phosphorylation during chronic opioid administration and their pharmacological influence

• Applicant: Dr. Andrea Kliewer
• Subject Area: Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 527494624

Opioids such as morphine and fentanyl mediate their effects via the μ-opioid receptor (MOP) and are the cornerstone of therapy for treatment of chronic pain. However, their clinical use is limited by severe adverse side effects e.g. respiratory depression, constipation, dependence, and tolerance. Abuse of opioids and the resulting fatal overdoses are a major public health problem worldwide. As a result, there is a great need for optimization in the opioid-based treatment of chronic pain. We have recently shown that MOP phosphorylation and desensitization play a crucial role in the development of analgesic tolerance. However, it is unclear whether the underlying molecular mechanism can also be transferred to the development of tolerance to other opioid effects such as respiratory depression. In our preliminary work, we have already shown that rapid GRK2/3-mediated MOP desensitization contributes to the development of tolerance whereas GRK5-mediated S375 phosphorylation leads to the development of addiction. The observed functional selectivity at the GRK level represents a new pharmacological target structure, which could be influenced by the use of specific GRK inhibitors. We have identified promising new highly selective GRK2 and GRK5 inhibitors that can be used to study opioid tolerance and dependence in vivo. Furthermore, we observed changes in the MOP phosphorylation pattern under chronic opioid treatment. Acute administration of highly potent opioids leads to phosphorylation of four S/T residues (T370, S375, T376 and T379), however after chronic treatment for several days all phosphorylation events are largely lost except for S375. Persistent S375 phosphorylation may lead to a permanently reduced responsiveness of the MOP. This could be a memory effect that contributes to opioid tolerance persisting in vivo for days to weeks. Our aim is to investigate whether this memory effect can be pharmacologically broken through. To answer these questions, we have a number of novel mouse models and phospho-specific antibodies at our disposal, which could contribute to the development of new therapeutic strategies in chronic pain therapy.

• DFG Programme: Research Grants