Grau James W, Huie J Russell, Garraway Sandra M, Hook Michelle A, Crown Eric D, Baumbauer Kyle M, Lee Kuan H, Hoy Kevin C, Ferguson Adam R
Cellular and Behavioral Neuroscience, Department of Psychology, Texas A&M University College Station, TX, USA.
Front Physiol. 2012 Aug 10;3:262. doi: 10.3389/fphys.2012.00262. eCollection 2012.
How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain.
伤害性信号在脊髓内如何被处理，以及这些信号是否会导致神经性疼痛的行为迹象，取决于它们与其他事件和行为的关系。我们的研究表明，这些关系会对脊髓可塑性产生持久影响，引发一种学习形式，改变后续伤害性刺激的效果。在脊髓横断的大鼠中，对其一后肢的胫骨前肌施加伤害性电击，以此来研究在没有大脑输入的情况下，低位脊髓系统的适应能力。如果每当腿部伸展时就施加电击（可控刺激），会导致屈曲持续时间增加，从而将净电击暴露降至最低。在接受与腿部位置无关的相同电击量的实验对象（不可控刺激）中，未观察到这种学习现象。这两种刺激形式对后续学习具有持久且不同的影响：可控刺激能促进学习，而不可控刺激则会抑制学习（学习缺陷）。不可控刺激还会增强机械反应性。我们回顾了相关证据，即可控刺激训练涉及一个依赖脑源性神经营养因子（BDNF）的过程，该过程既能预防又能逆转不可控电击的后果。我们将这些影响与BDNF蛋白和TrkB信号的变化联系起来。可控刺激还被证明可以对抗外周炎症（来自皮内辣椒素）的影响。我们提出了一个模型，假设伤害性输入在早期感觉阶段受到门控。这个门控对当前的环境关系（本体感觉和伤害性输入之间）敏感，从而使刺激能够被分类为可控或不可控。我们进一步提出，这个门控的状态受过去经验的影响，不可控刺激的历史会促进神经性疼痛的发展。
