Max Mitchell B, Wu Tianxia, Atlas Steven J, Edwards Robert R, Haythornthwaite Jennifer A, Bollettino Antonella F, Hipp Heather S, McKnight Colin D, Osman Inge A, Crawford Erin N, Pao Maryland, Nejim Jemiel, Kingman Albert, Aisen Daniel C, Scully Michele A, Keller Robert B, Goldman David, Belfer Inna
Clinical Pain Research Section, Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, MD, USA.
Mol Pain. 2006 Apr 19;2:14. doi: 10.1186/1744-8069-2-14.
Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year.
We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood--the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery.
Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.
疼痛患者常伴有抑郁和焦虑情绪，且与无痛患者相比，他们从精神药物治疗中获益更少。我们推测，这种部分耐药性是由于传入性疼痛投射通过脊髓 - 臂旁 - 下丘脑 - 杏仁核系统及其向其他情绪调节系统的投射，对情绪产生了独特的神经化学作用。针对疼痛患者的新型精神药物可能会以这类脑系统中的分子为靶点。我们提出一种方法，通过研究接受与疼痛缓解反应可变的外科手术患者队列中的多态性基因，来对分子靶点进行优先级排序。我们寻找在术后第一年中，在（1）手术疼痛缓解程度与（2）基因等位基因之间，在抑郁和焦虑方面显示出显著统计学相互作用的分子。
我们从缅因州腰椎研究中收集了280例因腰椎间盘突出症导致坐骨神经痛患者的DNA，其中162例接受了手术治疗，118例未接受手术治疗，该研究是一项大型前瞻性观察性研究，对这些患者进行了10年的随访。在手术使疼痛减轻>25%的患者中，用SF - 36心理健康量表评估的抑郁和焦虑症状在术后首次测量时迅速改善。在手术疼痛减轻很少或没有减轻的患者中，情绪评分平均保持不变。在每个残余疼痛水平上，个体间存在很大差异。三个预先指定的疼痛 - 情绪候选基因，儿茶酚 - O - 甲基转移酶（COMT）、5 - 羟色胺转运体和脑源性神经营养因子（BDNF）的多态性与术后晚期情绪或与情绪上的疼痛 - 基因相互作用无关。尽管样本量不足以有说服力地在更多基因中进行搜索，但对其他25个基因的探索性调查提供了术后情绪上疼痛 - 基因相互作用的示例——μ阿片受体与急性坐骨神经痛对情绪的短期影响有关，而甘丙肽 - 2受体与椎间盘切除术后未缓解疼痛对术后一年情绪的影响有关。
对接受缓解疼痛手术患者的疼痛、抑郁和焦虑进行纵向研究的基因组分析，可能有助于识别疼痛改变情绪所通过的分子。检测具有中等效应大小的等位基因将需要更大的队列。
