Department of Pain and Palliative Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo, Japan.
Pain Med. 2018 Feb 1;19(2):348-354. doi: 10.1093/pm/pnx102.
Despite the widespread use of opioids for the treatment of cancer pain, results from several surveys consistently show that pain is still prevalent in some patients with malignant diseases. The purinergic P2Y12 receptor is a primary site leading to microglial activation and hyperalgesic pain behaviors and is considered a key regulator in the prevention of the aggravation of clinical pain conditions. Genetic variability in the P2RY12 gene may contribute to individual differences in pain and opioid sensitivity.
We genotyped 31 single nucleotide polymorphisms (SNPs) throughout the P2RY12 gene and compared genotypes against pain measurements and opioid requirements in Japanese cancer pain patients (N = 90). The most promising SNP association with pain severity was validated by genotyping an additional postoperative pain patient cohort (N = 355).
Five SNPs (rs3732765, rs9859538, rs17283010, rs11713504, and rs10935840) of the P2RY12 gene were significantly associated with cancer pain severity, although opioid requirements were comparable in each genotype of the five SNPs. The alleles of these SNPs represented one absolute linkage disequilibrium block of the P2RY12 gene. In the second association study of postoperative pain, subjects carrying the minor T allele of the rs3732765 SNP demonstrated more intense 24-hour postoperative pain compared with subjects not carrying this allele although total 24-hour postoperative opioid consumptions based on weight were comparable.
Polymorphisms of the P2RY12 gene may predict individual differences in both cancer and postoperative pain severity; this might be caused by functional alteration of nociceptive neurons through neuron-glia interaction.
尽管阿片类药物被广泛用于治疗癌症疼痛，但几项调查的结果仍表明，恶性疾病患者仍存在疼痛。嘌呤能 P2Y12 受体是导致小胶质细胞激活和痛觉过敏疼痛行为的主要部位，被认为是预防临床疼痛加重的关键调节剂。P2RY12 基因的遗传多态性可能导致疼痛和阿片类药物敏感性的个体差异。
我们对 P2RY12 基因中的 31 个单核苷酸多态性（SNP）进行了基因分型，并将基因型与日本癌症疼痛患者的疼痛测量和阿片类药物需求进行了比较（N=90）。对与疼痛严重程度最相关的 SNP 进行了验证，对另一组术后疼痛患者（N=355）进行了基因分型。
P2RY12 基因的 5 个 SNP（rs3732765、rs9859538、rs17283010、rs11713504 和 rs10935840）与癌症疼痛严重程度显著相关，尽管在这 5 个 SNP 的每个基因型中，阿片类药物的需求是可比的。这些 SNP 的等位基因代表 P2RY12 基因的一个绝对连锁不平衡块。在术后疼痛的第二项关联研究中，与不携带该等位基因的受试者相比，携带 rs3732765 SNP 次要 T 等位基因的受试者在术后 24 小时疼痛更剧烈，尽管基于体重的 24 小时术后阿片类药物总消耗量相当。
P2RY12 基因的多态性可能预测癌症和术后疼痛严重程度的个体差异；这可能是通过神经元-胶质细胞相互作用导致伤害感受神经元的功能改变引起的。
