导读：有人对疼痛很敏感，有人不敏感，美国最新的一项研究发现，这与体内的P2RX7基因有关。
科学家在《自然—医学》上撰文称，P2RX7基因的遗传性变异会影响到不同人对疼痛的感受。因为疼痛感知的个体差异性和对疼痛缓解药物的反应不同，疼痛相关临床试验的进行一直都存在一定难度，这项研究或能有助我们在该基因变异的基础上开发出相应的个体疼痛疗法。
Jeff Mogil、Michael Salter等人观察了大量小鼠的不同疼痛敏感度，注意到小鼠P2RX7基因的突变与这些差异有关。他们发现该基因的某一变异让一种具有细胞膜中离子通道作用的受体P2X7生成大孔径；产生该基因变异的小鼠比未产生变异的小鼠会表现出更多疼痛，而一种能阻碍该大孔径生成的缩氨酸则可以减轻变异小鼠的疼痛。
之后，Salter和同事将该发现应用于人体试验，他们发现如果P2RX7基因的变异不导致P2X7受体生成大孔径的话，那么乳房切除术后疼痛和关节炎疼痛的患者会表现出较少的疼痛。
Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity
Robert E Sorge, Tuan Trang, Ruslan Dorfman, Shad B Smith, Simon Beggs, Jennifer Ritchie, Jean-Sebastien Austin, Dmitri V Zaykin, Heather Vander Meulen, Michael Costigan, Teri A Herbert, Merav Yarkoni-Abitbul, David Tichauer, Jessica Livneh, Edith Gershon, Ming Zheng, Keith Tan, Sally L John, Gary D Slade, Joanne Jordan, Clifford J Woolf, Gary Peltz, William Maixner, Luda Diatchenko, Ze'ev Seltzer
Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary1. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da2, 3. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.
文献链接：https://www.nature.com/nm/journal/v18/n4/full/nm.2710.html#/access
