Emerging immunotherapies with monoclonal antibodies against programmed cell death protein-1 (PD-1) have shown success in treating cancers. However, PD-1 signaling in neurons is largely unknown. We recently reported that dorsal root ganglion (DRG) primary sensory neurons express PD-1 and activation of PD-1 inhibits neuronal excitability and pain. Opioids are mainstay treatments for cancer pain, and morphine produces antinociception via mu opioid receptor (MOR). Here, we report that morphine antinociception and MOR signaling require neuronal PD-1. Morphine-induced antinociception after systemic or intrathecal injection was compromised in Pd1 -/- mice. Morphine antinociception was also diminished in wild-type mice after intravenous or intrathecal administration of nivolumab, a clinically used anti-PD-1 monoclonal antibody. In mouse models of inflammatory, neuropathic, and cancer pain, spinal morphine antinociception was compromised in Pd1 -/- mice. MOR and PD-1 are coexpressed in sensory neurons and their axons in mouse and human DRG tissues. Morphine produced antinociception by (i) suppressing calcium currents in DRG neurons, (ii) suppressing excitatory synaptic transmission, and (iii) inducing outward currents in spinal cord neurons; all of these actions were impaired by PD-1 blockade in mice. Loss of PD-1 also enhanced opioid-induced hyperalgesia and tolerance and potentiates opioid-induced microgliosis and long-term potentiation in the spinal cord in mice. Last, intrathecal infusion of nivolumab inhibited intrathecal morphine-induced antinociception in nonhuman primates. Our findings demonstrate that PD-1 regulates opioid receptor signaling in nociceptive neurons, leading to altered opioid-induced antinociception in rodents and nonhuman primates.

中文翻译：

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抗PD-1治疗会损害啮齿动物和非人类灵长类动物的阿片类药物抗伤害作用。

新兴的针对程序性细胞死亡蛋白-1（PD-1）单克隆抗体的免疫疗法已显示出成功治疗癌症的能力。但是，神经元中的PD-1信号很大程度上未知。我们最近报道，背根神经节（DRG）初级感觉神经元表达PD-1，PD-1的激活抑制神经元兴奋性和疼痛。阿片类药物是治疗癌症疼痛的主要方法，吗啡通过μ阿片类药物受体（MOR）产生抗伤害作用。在这里，我们报告吗啡抗伤害感受和MOR信号需要神经元PD-1。在Pd1-/-小鼠体内，全身或鞘内注射后，吗啡引起的抗伤害感受受到损害。在静脉或鞘内注射nivolumab（临床上使用的抗PD-1单克隆抗体）后，野生型小鼠中的吗啡抗伤害感受也有所减轻。在炎症性，神经性和癌性疼痛的小鼠模型中，Pd1-/-小鼠的脊髓吗啡镇痛作用受到损害。MOR和PD-1在小鼠和人类DRG组织中的感觉神经元及其轴突中共表达。吗啡通过（i）抑制DRG神经元中的钙电流，（ii）抑制兴奋性突触传递和（iii）诱导脊髓神经元中的外向电流来产生抗伤害作用。PD-1阻滞小鼠会削弱所有这些作用。PD-1的丢失还增强了阿片样物质诱导的痛觉过敏和耐受性，并增强了阿片样物质诱导的小鼠脊髓小胶质细胞增生和长期增强作用。最后，鞘内注射nivolumab在非人类灵长类动物中抑制鞘内吗啡诱导的抗伤害感受。