Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.
Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade.
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DOI：
10.1523/jneurosci.1564-11.2011
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发表时间：
2011-09-07
期刊：
影响因子：
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通讯作者：
Wei F
中科院分区：
文献类型：
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作者：
Gu M;Miyoshi K;Dubner R;Guo W;Zou S;Ren K;Noguchi K;Wei F
最近的研究表明，脑干头端延髓腹内侧区（RVM）的5-HT下行系统和脊髓背角的5-HT 3受体亚型参与了组织和神经损伤后下行痛易化的增强。然而，5-HT 3受体激活的机制及其对疼痛的促进作用仍不清楚。在本研究中，通过鞘内注射选择性5-HT 3受体激动剂SR 57227激活脊髓5-HT 3受体，诱导大鼠脊髓胶质细胞过度活跃、神经元过度兴奋和疼痛超敏反应。我们发现，存在通过趋化因子fractalkine的神经元到小胶质细胞的信号传导，通过细胞因子IL-18的小胶质细胞到星形胶质细胞的信号传导，通过IL-1β的星形胶质细胞到神经元的信号传导，以及脊髓背角中GluN（NMDA）受体的增强激活。此外，外源性BDNF诱导的下行痛易化伴随着在RVM中微量注射后脊髓背角中的CD 11b和GFAP表达的上调，这被脊髓5-HT 3受体的功能阻断显著地阻止。后爪炎症后脊髓CD 11b和GFAP的表达增强也通过RVM内Tph-2 shRNA干扰下行5-HT系统的分子耗竭而减弱。因此，这些研究结果提供了新的见解，在脊髓水平负责下降5-HT介导的疼痛促进组织和神经损伤后持续性疼痛的发展过程中的细胞和分子机制。新的疼痛治疗应该集中在下行易化诱导的胶质细胞参与的主要目标，特别是阻断神经元和胶质细胞之间的细胞间信号转导。
Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT3 receptor by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous BDNF-induced descending pain facilitation was accompanied with up-regulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, which were significantly prevented by functional blockade of spinal 5-HT3 receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.