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

环adp核糖（cADPR）是一种新型的Ca^<2+>-动员剂，参与许多细胞功能。然而，其在中枢神经系统中对伤害感觉的调节作用尚不清楚。本研究在小鼠脊髓中研究cADPR是否在疼痛传导中起一定作用。我们证明了cADPR是由CD38在细胞外合成的，通过核苷转运体（nt）转运到细胞中，然后Ca^<2+>通过fk506结合蛋白依赖过程被动员。这一过程可能与人类中性粒细胞的迁移和肾上腺染色质细胞中儿茶酚胺的释放有关。鞘内注射（i. t. injection） cADPR在0.01 ~ 5 nmol时引起触觉疼痛、触觉异常性痛，在1 nmol时反应峰值。cADPR诱导的触觉异常性痛可被一种cADPR拮抗剂8Br-cADPR阻断。NT抑制剂（肌苷、尿苷或NBT-1、S-（对硝基苯基）-6-硫代肌苷）、ryanodine受体拮抗剂（ryanodine）或SERCA泵选择性阻滞剂（thapsigargin）可保护小鼠免受cADPR诱导的异位性疼痛的诱导。脊髓中的CD38、NT和ryanodine受体可能参与了cadpr诱导的触觉异常性痛的机制。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。神经性疼痛对传统的镇痛药是难治性的，因此需要新的药物来治疗。在这项研究中，我们证明了静脉或静脉给药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深刻的抗疼痛作用。这些结果确立了CD38和NT作为神经性疼痛药物开发的靶分子。

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.