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

环状ADP-核糖(CADPR)是一种新型的钙动员剂，参与多种细胞功能。然而，它在中枢神经系统中调节伤害性感受的作用尚不清楚。在本研究中，我们研究了cADPR是否在小鼠脊髓痛觉传导中起一定作用。我们证明cADPR是由CD38细胞外合成的，通过核苷转运体(NTS)转运到细胞内，然后通过FK506结合蛋白依赖的过程来动员Ca~(2+)和Gt~(2+)。这一过程可能参与了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cADPR在0.01~5nmol处引起触觉疼痛，触觉超敏反应在1nmol处达到高峰。CADPR拮抗剂8BR-cADPR可阻断cADPR诱发的触觉超敏反应。NT抑制剂(肌苷、尿苷或NBT-1、S-对甲基苯基-6-硫代肌苷)、兰尼定受体拮抗剂(Ryanodine)或SERCA泵选择性阻断剂(Thapsigargin)对cADPR诱导的小鼠痛觉过敏有保护作用。脊髓CD38、NT和Ryanodine受体可能参与了cADPR诱发触觉超敏的机制。这也可能为了解神经病理性疼痛发生的潜在分子机制提供重要信息。神经病理性疼痛与传统止痛药相比是难治性的，因此需要新的药物来治疗。在本研究中，我们证明了静脉或腹腔注射8BR-cADPR、核苷转运蛋白抑制剂，或通过CD38 mRNA的小干扰RNA阻断脊髓CD38，在小鼠部分坐骨神经结扎模型和其他神经病理性和炎症性疼痛模型上都产生了显著的抗痛觉过敏作用。这些结果确立了CD38和NT作为开发治疗神经病理性疼痛药物的靶分子。

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.