Beta-endorphin is the key endogenous opioid influencing morphine µ-opioid receptor occupancy in rat hypothalamus: a binding kinetic model analysis.

The µ-opioid receptor (µ-OR) is the key target for morphine in the treatment of (chronic) pain. Endogenous opioids at the µ-OR have been implicated in multiple physiological processes, including pain relief. However, the extent to which µ-OR occupancy of morphine is influenced by endogenous opioids and µ-OR internalization is unclear. The aim of this study was to investigate the impact of endogenous opioids and µ-OR internalization on morphine µ-OR occupancy. To this end we developed a mathematical binding kinetic model incorporating information on binding kinetic parameters, µ-OR expression, µ-OR internalization rates, and levels of multiple endogenous opioids, in rat hypothalamus. µ-OR occupancies were simulated using morphine brain extracellular fluid concentration data, for different static levels of the endogenous opioids, including beta-endorphin, Dynorphin-A 1-17, Endomorphin-2, Leu-enkephalin, and Met-enkephalin. Simulations were performed in absence or presence of µ-OR internalization. We show that beta-endorphin has a strong impact on morphine µ-OR occupancy, followed by limited impact of met-enkephalin. Other endogenous opioids did not demonstrate any significant effect. µ-OR internalization reduced the impact of beta-endorphin on morphine µ-OR occupancy to a limited extent. We conclude that beta-endorphin plays an important role in morphine µ-OR occupancy, which could therefore play a key role in explaining interindividual variability in the analgesic effects of morphine. Finally, this study demonstrates the utility of a mathematical model workflow in deciphering the role of endogenous ligands in morphine's µ-OR occupancy.