生物谷：繼與人體冷知覺相關(guān)的基因“浮出水面”后,，科學(xué)家最近又確定了第一個(gè)直接與肌體癢知覺相關(guān)的基因。這一發(fā)現(xiàn)有望為新型抗瘙癢藥物的開發(fā)開辟新的道路,。相關(guān)論文7月25日在線發(fā)表于《自然》雜志,。
新發(fā)現(xiàn)的基因位于中央神經(jīng)系統(tǒng)，它可以產(chǎn)生“胃泌素釋放蛋白受體”（GRPR）,。許多科學(xué)家都試圖研究GRPR基因與疼痛知覺的相關(guān)性,，并沒有人將它與瘙癢聯(lián)系起來。
在最新的研究中,，由美國(guó)華盛頓大學(xué)醫(yī)學(xué)院的華人遺傳學(xué)家Zhou-Feng Chen領(lǐng)導(dǎo)的小組對(duì)GRPR基因進(jìn)行了深入的研究,。他們發(fā)現(xiàn)，GRPR僅存在于一些脊髓神經(jīng)元中,，而這些神經(jīng)細(xì)胞能夠?qū)⑼春桶W的信號(hào)傳遞給大腦,。進(jìn)一步的研究表明，肌體產(chǎn)生疼痛知覺并不一定需要GRPR蛋白受體——失去GRPR基因的小鼠仍然能夠?qū)崃?、炎癥和機(jī)械傷害產(chǎn)生疼痛反應(yīng),。
研究人員隨后對(duì)GRPR基因突變的小鼠注射了組胺等癢誘導(dǎo)物質(zhì)，從而確定了GRPR與癢知覺的相關(guān)性,。他們發(fā)現(xiàn),，突變小鼠不會(huì)像正常小鼠一樣到處亂撓。而當(dāng)正常小鼠被注射仿GRPR蛋白功能的物質(zhì)時(shí),，它們抓狂地更厲害了,。
許多疾病，包括皮膚病和腫瘤都會(huì)引起慢性瘙癢,，這是一項(xiàng)頑疾,，而新的發(fā)現(xiàn)無疑將為瘙癢患者帶來希望,。
美國(guó)加州大學(xué)戴維斯分校的神經(jīng)學(xué)家Earl Carstens和加拿大麥吉爾大學(xué)的遺傳學(xué)家Jeffrey Mogil都對(duì)新的研究成果表示了贊賞，他們一致認(rèn)為GRPR是一個(gè)“不同尋常的分子標(biāo)靶”,。（科學(xué)網(wǎng) 任霄鵬/編譯）
原始出處:
Nature advance online publication 25 July 2007 | doi:10.1038/nature06029; Received 4 August 2006; Accepted 18 June 2007; Published online 25 July 2007
A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord
Yan-Gang Sun1 & Zhou-Feng Chen1,2,3
Department of Anesthesiology,
Department of Molecular Biology and Pharmacology,
Department of Psychiatry, Washington University School of Medicine Pain Center, St Louis, Missouri 63110, USA
Correspondence to: Zhou-Feng Chen1,2,3 Correspondence and requests for materials should be addressed to Z.F.C. (Email: [email protected]).
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 dermatitis1, 2, 3. 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.
