The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration.
The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration.
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DOI：
10.1186/1471-2164-15-345
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发表时间：
2014-05-08
期刊：
影响因子：
4.4
通讯作者：
Clark JD
中科院分区：
文献类型：
--
作者：
Liang DY;Zheng M;Sun Y;Sahbaie P;Low SA;Peltz G;Scherrer G;Flores C;Clark JD
阿片类药物是治疗中度至重度疼痛的基石，但长期使用会导致适应不良，包括：耐受性、依赖性和阿片类药物引起的痛觉过敏 (OIH)。这些反应限制了阿片类药物的效用以及我们控制慢性疼痛的能力。尽管经过了数十年的研究，我们仍然没有治疗方法或行之有效的策略来克服这个问题。然而，基于小鼠单倍型的计算遗传图谱和通过分析全基因组序列数据（全基因组 HBCGM）生成的 SNP 数据库，为发现影响阿片类药物适应不良反应的新基因提供了一种无假设的方法。使用全基因组-HBCGM 分析从 23 个近交品系获得的吗啡诱导的耐受性、依赖性和痛觉过敏的表型数据。使用菌株子集分析遗传图谱结果的稳健性。此外，还检查了所有阿片类药物相关特征的分析结果。为了表征主要候选基因的功能作用，我们分析了转基因动物、行为不同的小鼠品系中的 mRNA 和蛋白质表达，以及脊髓组织中的免疫组织化学。我们的作图程序确定了 netrin-1 受体基因 (Dcc) 内的等位基因模式与 OIH 密切相关，并且它也与所分析的其他适应不良的阿片类药物特征的组合密切相关。 Dcc 基因杂合的成年小鼠患 OIH 的倾向显着降低，在长期接触吗啡后变得耐受或表现出依赖性。阿片类药物反应的差异并非由于脊髓组织中 Dcc 表达水平的基础或吗啡刺激差异所致，并且与成年动物脊髓或背根神经节的伤害性神经化学或解剖学改变无关。全基因组 HBCGM 是识别影响阿片类药物适应不良等生物医学特征的基因的强大工具。我们证明，Dcc 会影响慢性阿片类药物暴露后的耐受性、依赖性和 OIH，尽管不是通过成人脊髓中表达的简单差异。本文的在线版本（doi：10.1186/1471-2164-15-345）包含补充材料，可供授权用户使用。
Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses. Whole genome-HBCGM was used to analyze phenotypic data on morphine-induced tolerance, dependence and hyperalgesia obtained from 23 inbred strains. The robustness of the genetic mapping results was analyzed using strain subsets. In addition, the results of analyzing all of the opioid-related traits together were examined. To characterize the functional role of the leading candidate gene, we analyzed transgenic animals, mRNA and protein expression in behaviorally divergent mouse strains, and immunohistochemistry in spinal cord tissue. Our mapping procedure identified the allelic pattern within the netrin-1 receptor gene (Dcc) as most robustly associated with OIH, and it was also strongly associated with the combination of the other maladaptive opioid traits analyzed. Adult mice heterozygous for the Dcc gene had significantly less tendency to develop OIH, become tolerant or show evidence of dependence after chronic exposure to morphine. The difference in opiate responses was shown not to be due to basal or morphine-stimulated differences in the level of Dcc expression in spinal cord tissue, and was not associated with nociceptive neurochemical or anatomical alterations in the spinal cord or dorsal root ganglia in adult animals. Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord. The online version of this article (doi: 10.1186/1471-2164-15-345) contains supplementary material, which is available to authorized users.