Sun Yan-Gang, Chen Zhou-Feng
Department of Anesthesiology, Washington University School of Medicine Pain Center, St Louis, Missouri 63110, USA.
Nature. 2007 Aug 9;448(7154):700-3. doi: 10.1038/nature06029. Epub 2007 Jul 25.
Itching, or pruritus, is defined as an unpleasant cutaneous sensation that serves as a physiological self-protective mechanism to prevent the body from being hurt by harmful external agents. Chronic itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin diseases such as atopic dermatitis. The identity of the itch-specific mediator in the central nervous system, however, remains elusive. Here we describe that the gastrin-releasing peptide receptor (GRPR) plays an important part in mediating itch sensation in the dorsal spinal cord. We found that gastrin-releasing peptide is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, whereas expression of its receptor GRPR is restricted to lamina I of the dorsal spinal cord. GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses relative to wild-type mice. In contrast, induction of scratching behaviour was significantly reduced in GRPR mutant mice in response to pruritogenic stimuli, whereas normal responses were evoked by painful stimuli. Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behaviour in three independent itch models. These data demonstrate that GRPR is required for mediating the itch sensation rather than pain, at the spinal level. Our results thus indicate that GRPR may represent the first molecule that is dedicated to mediating the itch sensation in the dorsal horn of the spinal cord, and thus may provide a central therapeutic target for antipruritic drug development.
瘙痒，即瘙痒症，被定义为一种令人不适的皮肤感觉，它是一种生理自我保护机制，可防止身体受到有害外部因素的伤害。慢性瘙痒是由肾脏疾病、肝脏疾病以及几种严重的皮肤病（如特应性皮炎）引起的一个重大临床问题。然而，中枢神经系统中特异性瘙痒介质的身份仍然难以捉摸。在这里，我们描述了胃泌素释放肽受体（GRPR）在介导脊髓背角的瘙痒感觉中起重要作用。我们发现胃泌素释放肽在一小部分肽能背根神经节神经元中特异性表达，而其受体GRPR的表达仅限于脊髓背角的I层。与野生型小鼠相比，GRPR突变小鼠表现出相当的热、机械、炎症和神经性疼痛反应。相比之下，在GRPR突变小鼠中，对致痒刺激的搔抓行为诱导显著减少，而疼痛刺激则引发正常反应。此外，在三个独立的瘙痒模型中，直接向脊髓脑脊液注射GRPR拮抗剂可显著抑制搔抓行为。这些数据表明，在脊髓水平上，GRPR是介导瘙痒感觉而非疼痛所必需的。因此，我们的结果表明，GRPR可能是第一个专门介导脊髓背角瘙痒感觉的分子，从而可能为止痒药物开发提供一个核心治疗靶点。
