Budai D, Larson A A
Department of Veterinary PathoBiology, University of Minnesota, St. Paul 55108, USA.
Brain Res. 1996 Feb 26;710(1-2):197-203. doi: 10.1016/0006-8993(95)01384-9.
Substance P (SP) as well as excitatory amino acids (EAAs) appear to be released in response to stimulation of primary afferent C-fibers. Activity at N-methyl-D-aspartate (NMDA) receptors is essential for wind-up (the progressive potentiation of C-fiber-evoked responses of single neurons in response to an electrical stimulation), however, the role of SP in wind-up is unclear. To address this, the effects of iontophoretically applied CP-99,994 (a NK-1 receptor antagonist), SP and SP(1-7) (an N-terminal breakdown product of SP), were compared on responses of spinal dorsal horn wide dynamic range (WDR) neurons of the rat. Post-stimulus time histograms (PSTH) were summed over 12 responses to low frequency (0.5 Hz) electrical stimulation of the cutaneous receptive field. Changes in responses of dorsal horn neurons were evaluated by monitoring C-fiber input, wind-up, and the total number of spikes evoked by C-fiber activity in response to the 12 stimuli. The NK-1 receptor antagonist CP-99,994 significantly inhibited the total number of C-spikes and caused a significant reduction in wind-up without changing the C-fiber input, indicating the involvement of NK-1 receptors in wind-up. Application of SP led to an overall increase in the total number of C-fiber evoked responses of dorsal horn neurons and C-fiber input, however, wind-up, as defined, was significantly decreased following SP. In contrast, substance P(1-7) evoked a long-lasting increase in the total number of C-fiber-related spikes which was initially sustained by a transient increase in the input followed by a longer lasting increase in wind-up, an effect opposite that of CP-99,994. As NMDA activity has been previously shown to be inhibited and then potentiated by SP N-terminal activity over a similar time interval, the present data are consistent with the mediation of wind-up by NMDA and its modulation by SP N-terminal activity. Release of SP in response to noxious stimulation may, therefore, increase primary afferent C-fiber activity (input) whereas an accumulation of SP N-terminal metabolites appears to potentiate wind-up, perhaps via positive modulation of EAA activity.
P物质（SP）以及兴奋性氨基酸（EAA）似乎会在初级传入C纤维受到刺激时释放。N-甲基-D-天冬氨酸（NMDA）受体的活性对于wind-up（即单个神经元对电刺激的C纤维诱发反应的渐进性增强）至关重要，然而，SP在wind-up中的作用尚不清楚。为了解决这个问题，比较了离子电渗法应用CP-99,994（一种NK-1受体拮抗剂）、SP和SP(1-7)（SP的N端分解产物）对大鼠脊髓背角广动力范围（WDR）神经元反应的影响。对皮肤感受野进行低频（0.5 Hz）电刺激的12次反应的刺激后时间直方图（PSTH）进行求和。通过监测C纤维输入、wind-up以及C纤维活动在12次刺激下诱发的总尖峰数来评估背角神经元反应的变化。NK-1受体拮抗剂CP-99,994显著抑制了C尖峰的总数，并在不改变C纤维输入的情况下使wind-up显著降低，表明NK-1受体参与了wind-up。应用SP导致背角神经元C纤维诱发反应的总数和C纤维输入总体增加，然而，按照定义，SP作用后wind-up显著降低。相比之下，P物质(1-7)诱发了C纤维相关尖峰总数的持久增加，最初由输入的短暂增加维持，随后wind-up出现更持久的增加，这一效应与CP-99,994相反。由于先前已表明在相似的时间间隔内，NMDA活性会被SP N端活性抑制然后增强，目前的数据与NMDA介导wind-up及其受SP N端活性调节一致。因此，有害刺激引起的SP释放可能会增加初级传入C纤维的活动（输入），而SP N端代谢产物的积累似乎会增强wind-up，可能是通过对EAA活性的正向调节。
