An accelerating basic science literature is providing key insights into the mechanisms by which spinal neuropeptide Y (NPY) inhibits chronic pain. A key target of pain inhibition is the G_i-coupled neuropeptide Y1 receptor (Y1). Y1 is located in key sites of pain transmission, including the peptidergic subpopulation of primary afferent neurons and a dense subpopulation of small, excitatory, glutamatergic/somatostatinergic interneurons (Y1-INs) that are densely expressed in the dorsal horn, particularly in superficial lamina I-II. Selective ablation of spinal Y1-INs with an NPY-conjugated saporin neurotoxin attenuates the development of peripheral nerve injury-induced mechanical and cold hypersensitivity. Conversely, conditional knockdown of NPY expression or intrathecal administration of Y1 antagonists reinstates hypersensitivity in models of chronic latent pain sensitization. These and other results indicate that spinal NPY release and the consequent inhibition of pain facilitatory Y1-INs represent an important mechanism of endogenous analgesia. This mechanism can be mimicked with exogenous pharmacological approaches (e.g. intrathecal administration of Y1 agonists) to inhibit mechanical and thermal hypersensitivity and spinal neuron activity in rodent models of neuropathic, inflammatory, and postoperative pain. Pharmacological activation of Y1 also inhibits mechanical- and histamine-induced itch. These immunohistochemical, pharmacological, and cell type-directed lesioning data, in combination with recent transcriptomic findings, point to Y1-INs as a promising therapeutic target for the development of spinally directed NPY-Y1 agonists to treat both chronic pain and itch.

正在加速发展的基础科学文献正在为脊髓神经肽 Y (NPY) 抑制慢性疼痛的机制提供关键见解。疼痛抑制的一个关键目标是 G _i-偶联神经肽 Y1 受体 (Y1)。Y1 位于疼痛传递的关键部位，包括初级传入神经元的肽能亚群和小、兴奋性、谷氨酸能/生长抑素能中间神经元 (Y1-IN) 的密集亚群，它们在背角中密集表达，特别是在浅层 I -II. 用 NPY 偶联的皂草素神经毒素选择性消融脊髓 Y1-IN 可减轻周围神经损伤引起的机械和冷超敏反应的发展。相反，有条件地抑制 NPY 表达或鞘内注射 Y1 拮抗剂可恢复慢性潜伏痛敏化模型的超敏反应。这些和其他结果表明脊髓 NPY 的释放和随之而来的疼痛促进性 Y1-IN 的抑制代表了内源性镇痛的重要机制。这种机制可以用外源药理学方法来模拟（例如。Y1 激动剂鞘内给药）以抑制啮齿动物模型中的机械和热超敏反应以及脊髓神经元活动，包括神经性、炎症和术后疼痛。Y1 的药理学激活也抑制机械和组胺诱导的瘙痒。这些免疫组织化学、药理学和细胞类型导向的损伤数据，结合最近的转录组学发现，表明 Y1-INs 是开发脊髓定向 NPY-Y1 激动剂治疗慢性疼痛和瘙痒的有希望的治疗靶点。