Enhanced Analgesic Efficacy and Reduced Side Effects of Morphine by Combination with PD-1 Agonist.

Chronic pain is a debilitating disease and remains challenging to treat. Morphine serves as the most commonly used drug for the treatment of pathological pain. However, detrimental side effects (e.g., hyperalgesia and tolerance) manifest during chronic administration, thus counteracting morphine analgesia. Investigators have sought methods to widen the therapeutic window of morphine in the management of chronic pain. Programmed cell death protein 1 (PD-1) is a recently validated analgesic target and is coexpressed with the mu opioid receptor (μOR) in dorsal root ganglion (DRG) sensory neurons. Here, we present evidence that PD-1 regulates the expression of μOR mRNA and influences μOR-mediated analgesia. Notably, the concomitant administration of PD-1 agonist H-20 greatly reduces the dosage of morphine needed for analgesia, thereby significantly decreasing opioid-related side effects. This new combination therapy may provide a solution for managing chronic pain in patients who require morphine.