Cooper A H, Nie A A, Hedden N S, Herzog H, Taylor B K
Pittsburgh Center for Pain Research, Pittsburgh Project to end Opioid Misuse, Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
St Vincent's Centre for Applied Medical Research (AMR), Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia.
J Pain. 2025 May;30:105385. doi: 10.1016/j.jpain.2025.105385. Epub 2025 Mar 31.
Nerve damage induces a robust de novo expression of the pain-modulatory peptide neuropeptide Y (NPY) in large-diameter primary afferent neurons that innervate the dorsal horn of the spinal cord and the dorsal column nuclei. To determine whether this functions to modulate peripheral neuropathic pain in male and female mice, we selectively deleted the Npy gene in neurons of the dorsal root ganglion (DRG), without disruption of its expression in brain or dorsal horn neurons. We then subjected sensory neuron-specific NPY deletion mutant mice (Pirt-NPY) and their wild-type controls to either sham surgery, spared sural nerve injury (SNI) or spared tibial nerve injury (tSNI). Conditional Npy deletion did not change the severity or duration of static mechanical, dynamic mechanical, or cold allodynia in SNI or tSNI models, nor ongoing neuropathic pain as assessed with conditioned place preference to gabapentin. When injected after the resolution of tSNI-induced mechanical hypersensitivity (a latent pain sensitization model of chronic neuropathic pain), the NPY Y1 receptor-specific antagonist BIBO3304 equally reinstated mechanical hypersensitivity in Pirt-NPY mice and their wildtype controls. We conclude that nerve injury-induced upregulation of NPY in sensory neurons does not cause mechanical or cold hypersensitivity or ongoing pain, and that tonic inhibitory control of neuropathic pain by NPY in the spinal cord is mediated by release from dorsal horn interneurons rather than sensory neurons. PERSPECTIVE: This article answers the long-standing question as to whether nerve injury-induced upregulation of NPY in primary afferent neurons modulates neuropathic pain. We report that sensory neuron-specific NPY knockout did not change pain-like behaviors. CNS interneurons rather than sensory neurons likely mediate the well-documented phenomenon of spinal NPY analgesia.
神经损伤会诱导大直径初级传入神经元中痛觉调节肽神经肽Y（NPY）的强烈从头表达，这些神经元支配脊髓背角和背柱核。为了确定这是否对调节雄性和雌性小鼠的外周神经性疼痛起作用，我们选择性地删除了背根神经节（DRG）神经元中的Npy基因，而不破坏其在脑或背角神经元中的表达。然后，我们对感觉神经元特异性NPY缺失突变小鼠（Pirt-NPY）及其野生型对照进行假手术、保留腓肠神经损伤（SNI）或保留胫神经损伤（tSNI）。条件性Npy缺失并未改变SNI或tSNI模型中静态机械性、动态机械性或冷觉异常性疼痛的严重程度或持续时间，也未改变通过对加巴喷丁的条件性位置偏爱评估的持续性神经性疼痛。在tSNI诱导的机械性超敏反应（慢性神经性疼痛的潜伏性疼痛致敏模型）消退后注射时，NPY Y1受体特异性拮抗剂BIBO3304在Pirt-NPY小鼠及其野生型对照中同样恢复了机械性超敏反应。我们得出结论，神经损伤诱导的感觉神经元中NPY上调不会导致机械性或冷觉超敏或持续性疼痛，并且脊髓中NPY对神经性疼痛的紧张性抑制控制是由背角中间神经元而非感觉神经元释放介导的。观点：本文回答了一个长期存在的问题，即初级传入神经元中神经损伤诱导的NPY上调是否调节神经性疼痛。我们报告感觉神经元特异性NPY敲除并未改变疼痛样行为。中枢神经系统中间神经元而非感觉神经元可能介导了脊髓NPY镇痛这一有充分记录的现象。
