Anti-PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) are effective cancer immunotherapies.
• The role of PD-1 signaling in neuronal function, particularly in pain pathways, remains largely unexplored.
• Previous research indicated that PD-1 expression in primary sensory neurons inhibits neuronal excitability and pain.

Purpose of the Study:

• To investigate the role of neuronal programmed cell death protein-1 (PD-1) in mediating the analgesic effects of morphine.
• To determine if PD-1 signaling is required for mu opioid receptor (MOR) activation and antinociception.
• To examine the impact of PD-1 deficiency or blockade on various pain models and opioid-induced side effects.

Main Methods:

• Utilized knockout mice lacking PD-1 (Pd1-/-) and wild-type mice.
• Administered morphine systemically, intrathecally, and intravenously.
• Used nivolumab, an anti-PD-1 monoclonal antibody, to block PD-1 function.
• Assessed antinociception in mouse models of inflammatory, neuropathic, and cancer pain.
• Examined neuronal excitability, calcium currents, and synaptic transmission in dorsal root ganglion (DRG) neurons and spinal cord neurons.
• Investigated opioid-induced hyperalgesia, tolerance, microgliosis, and long-term potentiation.
• Conducted experiments in nonhuman primates.

Main Results:

• Morphine's antinociceptive effects were significantly reduced in Pd1-/- mice and in wild-type mice treated with nivolumab.
• PD-1 deficiency impaired morphine's ability to suppress calcium currents in DRG neurons and excitatory synaptic transmission.
• Loss of PD-1 enhanced opioid-induced hyperalgesia and tolerance, and potentiated spinal cord microgliosis and long-term potentiation.
• Intrathecal nivolumab administration blocked morphine-induced antinociception in nonhuman primates.
• PD-1 and MOR were found to be coexpressed in sensory neurons in both mouse and human DRG tissues.

Conclusions:

• Neuronal programmed cell death protein-1 (PD-1) is a critical regulator of mu opioid receptor (MOR) signaling and morphine-induced antinociception.
• PD-1 blockade or deficiency compromises opioid efficacy and exacerbates negative opioid-related effects, including hyperalgesia and tolerance.
• These findings reveal a novel link between the immune checkpoint PD-1 and opioid analgesia, with implications for pain management strategies.