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

环ADP核糖（cADPR）被认为是一种新型的Ca^<2+>动员剂，参与多种细胞功能。然而，其在中枢神经系统中介导伤害性感受的作用尚不清楚。在本研究中，cADPR是否在小鼠脊髓中的疼痛传导中起作用进行了研究。我们证明cADPR由CD 38在细胞外合成，通过核苷转运蛋白（NTs）转运到细胞内，然后通过FK 506结合蛋白依赖性过程动员Ca^2+。这一过程可能与人类中性粒细胞的迁移和肾上腺嗜铬细胞的儿茶酚胺释放有关。鞘内注射（i. t.注射）cADPR诱导触觉疼痛，触觉异常性疼痛在0.01至5纳摩尔，峰值响应在1纳摩尔。cADPR拮抗剂8 Br-cADPR可阻断cADPR诱导的触觉异常性疼痛。NT抑制剂（肌苷、尿苷或NBT-1、S-（对硝基苄基）-6-硫代肌苷）、ryanodine受体拮抗剂（ryanodine）或SERCA泵的选择性阻断剂（毒胡萝卜素）保护小鼠免受cADPR诱导的异常性疼痛的诱导。脊髓内的CD 38、NT和ryanodine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。神经性疼痛对常规镇痛药是难治的，因此需要新的药物用于治疗。在这项研究中，我们证明了静脉注射或i。t.给予8Br-cADPR、核苷转运蛋白抑制剂或通过CD 38 mRNA的小干扰RNA敲低脊髓CD 38在小鼠的部分坐骨神经结扎模型和其他神经性和炎性疼痛模型中产生了显著的抗异常性疼痛作用。这些结果确立了CD 38和NT作为用于开发神经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.