Evidence of a role for cyclic ADP-ribose in pain transduction in spinal cord

环 ADP-核糖在脊髓疼痛传导中作用的证据

基本信息

批准号：
18592036
负责人：
MORITA Katsuya
金额：
$ 2.52万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Cyclic ADP-ribose (cADPR), identified as a novel Ca^<2+>-mobilizing agent, has been involved in a many cellular functions. However, its role in mediation of nociception in central nervous system is unknown. In the present study, whether cADPR plays some role in pain transduction in the spinal cord was studied in mice. We demonstrated that cADPR was synthesized extracellularly by CD38, transported into the cells through nucleoside transporters (NTs), and then Ca^<2+> was mobilized by FK506-binding protein-dependent process. This process may be involved in migration in human neutrophils and in catecholamine release in adrenal chromaffin cells. Intrathecal injection (i. t. injection) of cADPR induced tactile pain, tactile allodynia at 0.01 to 5 nmole with a peak response at 1 nmole. Tactile allodynia induced by cADPR was blocked by a cADPR antagonist,8Br-cADPR. NT inhibitors (inosine, uridine or NBT-1, S-(p-notrobenzyl)-6-thioinosine), ryanodine receptor antagonist (ryanodine) or selective blocker of SERCA pump (thapsigargin) protected mice against the induction of allodynia induced by cADPR. CD38, NT and ryanodine receptor in the spinal cord may be involved in the mechanism of cADPR-induced tactile allodynia. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for treatment. In this study, we demonstrated that intravenous or i. t. administration of 8Br-cADPR, nucleoside transporter inhibitors, or knockdown of spinal CD38 by small interfering RNA of CD38 mRNA produced a profound antiallodynia effect in a partial sciatic nerve ligation model and other neuropathic and inflammatory pain models in mice. These results established CD38 and NT as the target molecules for the development of medicaments for neuropathic pain.

环状ADP-核糖(cADPR)被鉴定为新型Ca 2+ -动员剂，参与许多细胞功能。然而，其在中枢神经系统伤害感受介导中的作用尚不清楚。在本研究中，我们在小鼠身上研究了 cADPR 是否在脊髓疼痛传导中发挥一定作用。我们证明cADPR由CD38在细胞外合成，通过核苷转运蛋白(NT)转运到细胞内，然后通过FK506结合蛋白依赖性过程动员Ca ^ 2+ 。这一过程可能涉及人类中性粒细胞的迁移和肾上腺嗜铬细胞中儿茶酚胺的释放。鞘内注射（i.t.注射）cADPR在0.01至5 nmole处引起触觉疼痛、触觉异常性疼痛，在1 nmole处出现峰值响应。 cADPR 诱导的触觉异常性疼痛可被 cADPR 拮抗剂 8Br-cADPR 阻断。 NT 抑制剂（肌苷、尿苷或 NBT-1、S-（对非苄基）-6-硫代肌苷）、兰尼碱受体拮抗剂（ryanodine）或 SERCA 泵选择性阻断剂（thapsigargin）可保护小鼠免受 cADPR 诱导的异常性疼痛。脊髓中的CD38、NT和兰尼碱受体可能参与cADPR诱导的触觉异常性疼痛的机制。这也可能为理解神经性疼痛发展的潜在分子机制提供重要信息。神经性疼痛对于常规镇痛药是难以治疗的，因此需要新的药物来治疗。在这项研究中，我们证明了静脉注射或注射。 t。给予 8Br-cADPR、核苷转运蛋白抑制剂或通过 CD38 mRNA 的小干扰 RNA 敲低脊髓 CD38，在小鼠的部分坐骨神经结扎模型和其他神经性和炎症性疼痛模型中产生了显着的抗异常疼痛效果。这些结果确立了 CD38 和 NT 作为开发神经性疼痛药物的靶分子。