Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

译文

:越来越多的证据表明,Toll样受体(TLR)信号转接头蛋白与感觉神经元中存在的Toll / Interleukin-1受体(TIR)域相互作用可能会调节神经性疼痛状态。配体与TLR相互作用后,TIR既可以启动细胞内信号传导,也可以促进信号传导衔接子蛋白募集到胞质内域。尽管TLR TIR是许多TLR信号级联反应的核心,但对其在感觉神经元中的作用知之甚少。在这项研究中,我们调查了TLR TIR诱饵肽修饰为包含TAT序列(HIV转录基因的反式激活因子; TAT-4BB)在多大程度上影响LPS诱导的细胞内钙通量和感觉神经元的兴奋,以及行为改变对TLR4活性代谢产物吗啡-3-葡糖醛酸(M3G)的体内暴露。 TAT-4BB抑制了LPS诱导的大多数感觉神经元中钙的变化,并降低了小直径神经元中LPS依赖性神经元的兴奋性。 TAT-4BB的急性全身给药以剂量依赖的方式逆转了M3G诱导的触觉异常性疼痛,但并未影响运动活动,焦虑或对有害热刺激的反应。这些数据表明,靶向TLR TIR结构域可以提供新颖的药理学靶标,以减少或逆转啮齿动物中TLR4依赖性的疼痛行为。

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