Wieskopf Jeffrey S, Mathur Jayanti, Limapichat Walrati, Post Michael R, Al-Qazzaz Mona, Sorge Robert E, Martin Loren J, Zaykin Dmitri V, Smith Shad B, Freitas Kelen, Austin Jean-Sebastien, Dai Feng, Zhang Jie, Marcovitz Jaclyn, Tuttle Alexander H, Slepian Peter M, Clarke Sarah, Drenan Ryan M, Janes Jeff, Al Sharari Shakir, Segall Samantha K, Aasvang Eske K, Lai Weike, Bittner Reinhard, Richards Christopher I, Slade Gary D, Kehlet Henrik, Walker John, Maskos Uwe, Changeux Jean-Pierre, Devor Marshall, Maixner William, Diatchenko Luda, Belfer Inna, Dougherty Dennis A, Su Andrew I, Lummis Sarah C R, Imad Damaj M, Lester Henry A, Patapoutian Ardem, Mogil Jeffrey S
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Sci Transl Med. 2015 May 13;7(287):287ra72. doi: 10.1126/scitranslmed.3009986.
Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of α6* (α6-containing) nAChRs by analyzing both gain- and loss-of-function mutants. We find that mechanical allodynia associated with neuropathic and inflammatory injuries is significantly altered in α6* mutants, and that α6* but not α4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6's role in analgesia is at least partially due to direct interaction and cross-inhibition of α6* nAChRs with P2X2/3 receptors in DRG nociceptors. Finally, we establish the relevance of our results to humans by the observation of genetic association in patients suffering from chronic postsurgical and temporomandibular pain.
慢性疼痛是一个极为普遍且管理不善的人类健康问题。我们利用基于微阵列的表达基因组学技术，对25个近交系小鼠品系进行研究，以确定背根神经节（DRG）中表达的基因对机械性异常疼痛（慢性疼痛的一个突出症状）的影响。我们发现，编码烟碱型乙酰胆碱受体（nAChR）α6亚基的Chrna6的表达水平与异常疼痛高度相关。通过分析功能获得型和功能缺失型突变体，我们证实了α6*（含α6）nAChRs的重要性。我们发现，与神经病理性和炎症性损伤相关的机械性异常疼痛在α6突变体中显著改变，并且外周和/或脊髓尼古丁镇痛绝对需要α6而非α4烟碱型受体。此外，我们表明Chrna6在镇痛中的作用至少部分归因于α6 nAChRs与DRG伤害感受器中的P2X2/3受体的直接相互作用和交叉抑制。最后，通过观察慢性术后疼痛和颞下颌疼痛患者的遗传关联，我们确定了我们的研究结果与人类的相关性。
