ABCB1基因多态性与冷压痛反应：接受美沙酮维持治疗的阿片类药物依赖患者。
ABCB1 Polymorphisms and Cold Pressor Pain Responses: Opioid-Dependent Patients on Methadone Maintenance Therapy.
作者信息
Zahari Zalina, Lee Chee Siong, Ibrahim Muslih Abdulkarim, Musa Nurfadhlina, Mohd Yasin Mohd Azhar, Lee Yeong Yeh, Tan Soo Choon, Mohamad Nasir, Ismail Rusli
机构信息
Zalina Zahari, MSc, is Pharmacist, Department of Pharmacy, Hospital Universiti Sains Malaysia, and Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Chee Siong Lee, MMed, is Emergency Medicine Specialist, Department of Emergency Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Muslih Abdulkarim Ibrahim, PhD, is Senior Lecturer, Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Hawler, Iraq. Nurfadhlina Musa, MSc, is Senior Research Officer, Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Mohd Azhar Mohd Yasin, MMed, is Psychiatrist, Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Mohd Azhar Mohd Yasin, MMed, is Psychiatrist, Department of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Yeong Yeh Lee, PhD, is Professor, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Soo Choon Tan, PhD, is Professor, Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Nasir Mohamad, PhD, is Professor, Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, Malaysia. Rusli Ismail, PhD, is Professor, Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.
出版信息
Nurs Res. 2017 Mar/Apr;66(2):134-144. doi: 10.1097/NNR.0000000000000204.
BACKGROUND
Methadone is a substrate of the P-glycoprotein efflux transporter, which is encoded by ABCB1 (MDR1), and thus, ABCB1 polymorphisms may influence the transport of methadone at the blood-brain barrier, affecting its adverse effects.
OBJECTIVES
This study investigated the association between ABCB1 polymorphisms and cold pressor pain responses among opioid-dependent patients on methadone maintenance therapy (MMT).
METHODS
Malay male opioid-dependent patients receiving MMT (n = 148) were recruited. Cold pressor pain responses (pain threshold, pain tolerance, and pain intensity) were measured at 0, 2, 4, 8, 12, and 24 hours post-methadone dose. DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms including 1236C>T (rs1128503), 2677G>T/A (rs2032582), and 3435C>T (rs1045642) using the allelic discrimination real-time polymerase chain reaction. Repeated-measure analysis of variance between-group analysis was used to compare the three cold pressor pain responses and ABCB1 polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) according to genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes.
RESULTS
Patients with 2677 GG or 2677G allele had the lowest pain threshold compared with 2677G>T/A genotypes or alleles (p = .007 and .002, respectively). Haplotype analysis showed a significant association between ABCB1 haplotypes and pain threshold (p = .02). Patients with 2677G allele had the lowest pain tolerance compared to those with 2677T and 2677A alleles (2677G < 2677T < 2677A allele carriers; p = .05). In terms of pain intensity scores, patients with 2677 GG or 2677G allele had the highest scores compared to other 2677G>T/A genotypes or alleles (p = .04 and .008, respectively). Haplotype analysis revealed a significant difference between patients with CGC haplotype and those without this haplotype (p = .02).
DISCUSSION
To the best of our knowledge, this study provides the first evidence that ABCB1 polymorphisms are associated with cold pressor pain responses among Malay male patients with opioid dependence on MMT. The results may provide an initial prediction on heightened pain sensitivity or hyperalgesia for individuals who are carriers of the ABCB1 polymorphisms.
背景
美沙酮是P-糖蛋白外流转运体的底物，该转运体由ABCB1（MDR1）编码，因此，ABCB1基因多态性可能会影响美沙酮在血脑屏障的转运，进而影响其不良反应。
目的
本研究调查了ABCB1基因多态性与接受美沙酮维持治疗（MMT）的阿片类药物依赖患者冷加压疼痛反应之间的关联。
方法
招募接受MMT的马来男性阿片类药物依赖患者（n = 148）。在美沙酮给药后0、2、4、8、12和24小时测量冷加压疼痛反应（疼痛阈值、疼痛耐受力和疼痛强度）。从全血中提取DNA，并使用等位基因鉴别实时聚合酶链反应对ABCB1基因多态性进行基因分型，包括1236C>T（rs1128503）、2677G>T/A（rs2032582）和3435C>T（rs1045642）。采用组间重复测量方差分析，根据基因型和等位基因加性模型、基因型显性和隐性模型、单倍型和双倍型比较三种冷加压疼痛反应和ABCB1基因多态性（1236C>T、2677G>T/A和3435C>T）。
结果
与2677G>T/A基因型或等位基因相比，2677 GG或2677G等位基因的患者疼痛阈值最低（分别为p = 0.007和0.002）。单倍型分析显示ABCB1单倍型与疼痛阈值之间存在显著关联（p = 0.02）。与携带2677T和2677A等位基因的患者相比，携带2677G等位基因的患者疼痛耐受力最低（2677G < 2677T < 2677A等位基因携带者；p = 0.05）。在疼痛强度评分方面，与其他2677G>T/A基因型或等位基因相比，2677 GG或2677G等位基因的患者评分最高（分别为p = 0.04和0.008）。单倍型分析显示，携带CGC单倍型的患者与未携带该单倍型的患者之间存在显著差异（p = 0.02）。
讨论
据我们所知，本研究首次提供证据表明，ABCB1基因多态性与接受MMT的马来男性阿片类药物依赖患者的冷加压疼痛反应相关。研究结果可能为ABCB1基因多态性携带者的疼痛敏感性增强或痛觉过敏提供初步预测。
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