Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain
Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain
复制标题
DOI：
10.1016/j.pain.2007.09.020
复制
发表时间：
2008-07-15
期刊：
影响因子：
7.4
通讯作者：
Suzuki, Hidenori
中科院分区：
文献类型：
--
作者：
Sakai, Atsushi;Asada, Minoru;Suzuki, Hidenori
由于神经性疼痛对常规镇痛药如阿片类和非甾体抗炎药具有抗性，因此一直在等待开发用于其治疗的新型药物。与伤害感受相关的几个关键分子已被认为是新镇痛药的潜在靶点。胶质细胞系源性神经营养因子（GDNF）具有多种影响特定神经细胞群的存活和发育的功能，其通过与其高亲和力受体GFR α 1结合并随后激活酪氨酸受体激酶RET、神经细胞粘附分子（NCAM）或其他信号分子而介导细胞内信号的传递。GDNF在啮齿类动物神经病理性疼痛模型中也表现出镇痛作用，尽管其潜在的机制仍在很大程度上未知，包括所涉及的细胞内信号转导。我们在此报道NCAM信号在慢性缩窄性损伤大鼠中介导GDNF的镇痛作用中起作用。我们发现NCAM在脊髓背角的内在神经元和具有小胞体的背根节神经元中表达。CCI大鼠给予NCAM反义寡核苷酸减少NCAM表达，可在不影响RET信号激活的情况下消除GDNF的镇痛作用。NCAM模拟肽CM部分减轻CCI诱导的慢性疼痛。这些发现表明，NCAM信号在GDNF的镇痛作用中起着关键作用，并且开发激活GDNF-NCAM信号的新药可能代表了缓解顽固性疼痛的新策略。(c)2007年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Since neuropathic pain is resistant to conventional analgesics such as opiates and non-steroidal anti-inflammatory drugs, the development of new types of drugs for its treatment has been awaited. Several key molecules associated with nociception have been suggested as potential targets for new analgesics. Glial cell line-derived neurotrophic factor (GDNF) has a variety of functions affecting the survival and development of specified neural cell populations, mediated via transmission of intracellular signals through binding to its high-affinity receptor, GFR alpha 1, and subsequent activation of a tyrosine receptor kinase, RET, neural cell adhesion molecule (NCAM), or other signaling molecules. GDNF also exhibits analgesic effects in rodent models of neuropathic pain, although the underlying mechanisms are still largely unknown, including the intracellular signal transduction involved. We report here that NCAM signaling plays a role in mediating the analgesic effect of GDNF in rats with chronic constrictive injury (M). We found that NCAM was expressed in intrinsic neurons in the spinal dorsal horn and in dorsal root ganglion neurons with small cell bodies. Reduction of NCAM expression by NCAM antisense oligodeoxynucleotide administration to CCI rats abolished the analgesic effect of GDNF without affecting RET signaling activation. An NCAM mimetic peptide, CM, partially reduced the chronic pain induced by CCI. These findings suggest that NCAM signaling plays a critical role in the analgesic effect of GDNF and that development of new drugs activating GDNF-NCAM signaling may represent a new strategy for the relief of intractable pain. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.