肾上腺髓质素(Adrenomedullin)在神经病理性疼痛中的作用及其机制

Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and was recently demonstrated to be a pain-related peptide. Our group has found that AM is involved in the pathogenesis of inflammatory pain and morphine tolerance. The pilot studies in our laboratory showed that mRNA or protein of AM was upregulated in the dorsal root ganglia (DRG) and spinal dorsal horn. Particularly, intrathecal administration of the AM receptor antagonist AM22-52 inhibited mechanical allodynia evoked by peripheral nerve injury. These results suggest that the increase in AM receptor signaling at DRG and spinal levels underlies neuropathic pain. The present project is aimed to investigate the mechanisms underlying AM’s involvement in neuropathic pain by characterizing spatio-temporal expression of AM, determining the relationship between the enhanced AM receptor signaling and the sensitization of DRG and spinal dorsal horn neurons or the activation of glial cells following peripheral nerve injury.

肾上腺髓质素(adrenomedullin，AM)是CGRP家族的成员，是近年证实的痛介质。我们组观察到AM在炎性痛和吗啡耐受的发病中起重要作用。最近预实验显示，外周神经损伤后，背根神经节(DRG)和脊髓背角的AM mRNA或蛋白增加；鞘内给予AM受体阻断剂AM22-52抑制神经损伤诱发的触觉超敏。提示DRG和背角AM活动增加可能是神经病理性痛(Neuropathic pain，NP)新的发病机制。本项目拟检查外周神经损伤后AM表达的时间-空间特点；检测NP发生时，AM活动增加和DRG、脊髓背角中神经元敏感化、胶质细胞激活的关系，从而探讨AM参与NP的细胞学机制。

肾上腺髓质素(adrenomedullin，AM)是近年证实的痛介质。本项目显示，外周神经损伤能诱发在受损伤神经纤维和邻近未受损伤神经纤维、受损伤神经所传入的DRG和邻近未受损伤的DRG以及脊髓背角中AM和RAMP2表达增加。而阻断脊髓AM受体则抑制神经损伤诱发的机械痛觉。AM活动增强使脊髓背侧神经元痛分子nNOS、c-Fos和磷酸化ERK表达增加，激活DRG卫星胶质细胞，增加IL-1β、pCREB和pNF-κB产生。这就证实了，AM通过激活脊髓背侧和/或DRG中神经元和胶质细胞的机制，诱发神经病理性痛发生。本项目揭示了神经病理性痛的神经生物学机制；为理解痛觉形成原理、探讨神经病理性痛的临床治疗打开了新的路径。