PT  - JOURNAL ARTICLE
AU  - Zilong Wang
AU  - Changyu Jiang
AU  - Qianru He
AU  - Megumi Matsuda
AU  - Qingjian Han
AU  - Kaiyuan Wang
AU  - Sangsu Bang
AU  - Ru-Rong Ji
TI  - Morphine analgesia and μ opioid receptor signaling require programed death protein 1
AID  - 10.1101/580506
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 580506
4099  - http://biorxiv.org/content/early/2019/03/17/580506.short
4100  - http://biorxiv.org/content/early/2019/03/17/580506.full
AB  - Opioids such as morphine produce analgesia via mu opioid receptor (MOR), but opioid receptor signaling is not fully understood. Here we report that morphine analgesia and MOR signaling require neuronal Programmed cell death protein-1 (PD-1). We found that morphine-induced antinociception following systemic or intrathecal injection was compromised in Pd1-/- mice. Morphine analgesia was also abrogated in wild-type mice after treatment with Nivolumab, a clinically used anti-PD-1 monoclonal antibody. Morphine produced analgesia by suppressing calcium currents in DRG neurons and excitatory synaptic transmission in spinal cord neurons, but strikingly, both actions were impaired by PD-1 blockade. In a mouse model of bone cancer, the antinociceptive action of systemic morphine was compromised in Pd1-/- mice. Finally, PD-L1 and morphine produce synergistic analgesia. Our findings demonstrate that PD-1 also acts as a neuro checkpoint inhibitor and mediates opioid-induced analgesia and MOR signaling in neurons.