Transection of the sural and common peroneal branches of the sciatic nerve produces cutaneous hypersensitivity at the tibial innervation territory of the mouse hindpaw that resolves within a few weeks. We report that interruption of endogenous neuropeptide Y (NPY) signaling during remission, with either conditional NPY knockdown in NPYtet/tet mice or intrathecal administration of the Y1 receptor antagonist BIBO3304, reinstated hypersensitivity. These data indicate that nerve injury establishes a long-lasting latent sensitization of spinal nociceptive neurons that is masked by spinal NPY-Y1 neurotransmission. To determine whether this mechanism extends beyond the sensory component of nociception, we used conditioned place aversion and preference assays to evaluate the affective component of pain. We found that BIBO3304 produced place aversion in mice when administered during remission. Furthermore, the analgesic drug gabapentin produced place preference after NPY knockdown in NPYtet/tet but not control mice. We then used pharmacological agents and deletion mutant mice to investigate the cellular mechanisms of neuropathic latent sensitization. BIBO3304-induced reinstatement of mechanical hypersensitivity and conditioned place aversion could be prevented with intrathecal administration of an N-methyl-d-aspartate receptor antagonist (MK-801) and was absent in adenylyl cyclase type 1 (AC1) deletion mutant mice. BIBO3304-induced reinstatement could also be prevented with intrathecal administration an AC1 inhibitor (NB001) or a TRPV1 channel blocker (AMG9801), but not vehicle. Intrathecal administration of a TRPA1 channel blocker (HC030031) prevented the reinstatement of neuropathic hypersensitivity produced either by BIBO3304, or by NPY knockdown in NPYtet/tet but not control mice. Our results confirm new mediators of latent sensitization: TRPA1 and TRPV1. We conclude that NPY acts at spinal Y1 to tonically inhibit a molecular NMDAR➔AC1 intracellular signaling pathway in the dorsal horn that is induced by peripheral nerve injury and drives both the sensory and affective components of chronic neuropathic pain.

中文翻译：

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神经肽 Y 抑制慢性神经性疼痛情感维度的 NMDAR➔AC1➔TRPA1/TRPV1 机制

坐骨神经的腓肠和腓总支的横断在小鼠后爪的胫骨神经支配区域产生皮肤超敏反应，并在几周内消退。我们报告说，在缓解期间内源性神经肽 Y (NPY) 信号传导的中断，在 NPYtet/tet 小鼠中有条件的 NPY 敲低或 Y1 受体拮抗剂 BIBO3304 的鞘内给药，恢复了超敏反应。这些数据表明，神经损伤建立了脊髓 NPY-Y1 神经传递所掩盖的脊髓伤害性神经元的长期潜伏致敏。为了确定这种机制是否超出了伤害感受的感觉成分，我们使用条件性地方厌恶和偏好分析来评估疼痛的情感成分。我们发现 BIBO3304 在缓解期间给药时会在小鼠中产生位置厌恶。此外，镇痛药加巴喷丁在 NPYtet/tet 中 NPY 敲低后产生了位置偏好，但在对照小鼠中没有。然后，我们使用药物制剂和缺失突变小鼠来研究神经性潜在致敏的细胞机制。通过鞘内注射 N-甲基-d-天冬氨酸受体拮抗剂 (MK-801) 可以防止 BIBO3304 诱导的机械超敏反应和条件性位置厌恶的恢复，并且在腺苷酸环化酶 1 型 (AC1) 缺失突变小鼠中不存在。也可以通过鞘内注射 AC1 抑制剂 (NB001) 或 TRPV1 通道阻滞剂 (AMG9801) 来预防 BIBO3304 诱导的恢复，但不能通过载体进行预防。鞘内注射 TRPA1 通道阻滞剂 (HC030031) 可防止 BIBO3304 或 NPYtet/tet 中 NPY 敲低产生的神经性超敏反应的恢复，但不能阻止对照小鼠。我们的结果证实了潜在致敏的新介质：TRPA1 和 TRPV1。我们得出结论，NPY 作用于脊髓 Y1，以强直地抑制背角中分子 NMDAR➔AC1 细胞内信号通路，该通路由外周神经损伤诱导，并驱动慢性神经性疼痛的感觉和情感成分。