Duric Vanja, McCarson Kenneth E
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160 USA.
Mol Pain. 2007 Oct 31;3:32. doi: 10.1186/1744-8069-3-32.
Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB), while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.
持续性疼痛通过激活各种伤害性机制，在中枢神经系统（CNS）的感觉通路中产生复杂的改变。然而，疼痛对高级脑中枢的影响，尤其是疼痛的应激成分对边缘系统的影响，目前了解甚少。神经激肽-1（NK-1）受体和脑源性神经营养因子（BDNF）是已知的痛觉过敏和脊髓中枢敏化的神经介质，在暴露于各种应激源期间，海马结构中发生的可塑性和神经变性中也有涉及。本研究结果表明，在后爪注射完全弗氏佐剂（CFA）可增加同侧背角中NK-1受体和BDNF mRNA水平，支持这些伤害性介质在增强上行疼痛信号传导中起重要作用。在海马中观察到相反的效果，CFA下调了NK-1受体和BDNF基因表达，这一现象先前在应激和抑郁的固定模型中也有观察到。蛋白质印迹分析表明，在脊髓中，CFA还增加了磷酸化的环磷酸腺苷反应元件结合蛋白（CREB）的水平，而在海马中，该转录因子的激活显著降低，进一步表明NK-1或BDNF基因的组织特异性转录可能部分受通过激活CREB介导的常见细胞内转导机制调节。这些发现表明，持续性伤害感受在CNS中诱导NK-1受体和BDNF基因表达以及CREB激活的差异性区域调节，这可能反映了这些神经调节剂在持续性感觉激活期间在脊髓中的不同作用，以及对诸如海马等高级脑结构的调节作用。
