近五分之一的人患有慢性疼痛,慢性疼痛是指持续一个月以上(以前为三个月或半年)的疼痛,也有人把慢性疼痛比喻为一种不死的癌症。目前,中国至少有一亿以上的慢性疼痛患者。
在过去二十年中,对于慢性痛苦的了生物学研究获得的了许多突破,但问题仍很多。治疗慢性疼痛的一个主要挑战就是要弄清楚为什么某些人会患慢性疼痛。弄清楚这一点有助于制定特定患者人群的个性化治疗策略。
研究结果发表在《自然医学》杂志上。蒙特利尔的麦吉尔大学教授Jeffrey Mogil和多伦多大学附属医院的Michael Salter教授领导的研究小组确定了影响慢性疼痛敏感性的一个重要基因。研究结果还表明一种个性化治疗慢性疼痛的新方法。
研究人员发现编码疼痛受体的基因是P2X7受体。具体来说,科学家发现P2X7中一个单一氨基酸的变化控制引起慢性疼痛的两个主要原因的灵敏度:炎症和神经损伤。
众所周知,氨基酸的变化只会影响P2X7受体形成的毛孔让大型分子通过的功能,但不影响该受体其他功能,这一点允许多离子通过。使用靶向作用于孔隙形成的一种肽,研究人员发现疼痛会大大减少。
然后科学家研究了两种不同类型的持续性疼痛患者之间的遗传差异:慢性乳房切除手术后疼痛和骨关节炎。在这两种情况下他们发现,P2X7受体基因遗传变异后孔隙形成率较低的人,疼痛程度较低。
麦吉尔大学疼痛研究员Mogil, E.P. Taylor教授说:“我们的研究结果表明有可能开发出一种药物能阻塞这个关键受体的毛孔,而不影响该受体的其他功能,从而发挥止痛作用,同时尽量减少副作用。
Salter、Anne教授和SickKids的Tanenbaum分子医学主席Max表示:这些发现有助于慢性疼痛个体化治疗的发展。美国和以色列的科学家们也参与这项研究。
这项研究是由Krembil基金会、路易丝和艾伦·爱德华兹基金会、美国国立卫生研究院(NIH)加拿大健康研究所(CIHR)和SickKids基金会研究院资助。(生物谷:Bioon)
doi:10.1038/nm.2710
PMC:
PMID:
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, Michael W Salter, Jeffrey S Mogil.
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.