Radhakrishnan V, Iyengar S, Henry J L
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Neuroscience. 1998 Apr;83(4):1251-60. doi: 10.1016/s0306-4522(97)00313-8.
The effects of novel substance P (NK-1) receptor antagonists LY303870 and LY306740, as well as LY306155, the enantiomer of LY303870, were tested on the responses of nociceptive spinal dorsal horn neurons to iontophoretically applied substance P and to peripheral noxious stimuli. The peripheral stimuli included noxious thermal and pinch stimuli applied to the cutaneous receptive field in the hind paw and stimulation of the superficial peroneal nerve with a train of high-intensity electrical stimuli. Extracellular recordings were obtained using multi-barrel electrodes from L4-L7 segments of the spinal cord in cats anaesthetized with alpha-chloralose and spinalized at the L1 level. The antagonists were given i.v. (0.5-4.0 mg/kg). Responses to substance P were inhibited by LY303870 and by LY306740 in a dose-related manner, but were not affected by LY306155. Responses to peripheral noxious thermal stimulation were inhibited in a dose-related manner by LY303870 and LY306740, and only at higher doses (2 mg/kg or more) by LY306155. Responses to pinch stimuli were inhibited by LY303870 and LY306740. LY306155 lacked consistent effects on pinch responses. LY303870 selectively inhibited the late component of the response to electrical stimulation of the superficial peroneal nerve. When these three drugs were tested against the responses of dorsal horn neurons to the excitatory amino acid, N-methyl-D-aspartate, the responses were unaffected. These data suggest that LY303870 and LY306740 pass from the circulation into the spinal cord where they antagonize dorsal horn neuronal responses to substance P and nociceptive inputs.
新型P物质（NK-1）受体拮抗剂LY303870和LY306740以及LY303870的对映体LY306155，在伤害性脊髓背角神经元对离子导入施加的P物质和外周伤害性刺激的反应上进行了测试。外周刺激包括施加于后爪皮肤感受野的伤害性热刺激和夹捏刺激，以及用一串高强度电刺激刺激腓浅神经。在以α-氯醛糖麻醉并在L1水平脊髓横断的猫中，使用多管电极从脊髓L4-L7节段进行细胞外记录。拮抗剂通过静脉注射给药（0.5 - 4.0mg/kg）。LY303870和LY306740以剂量相关的方式抑制对P物质的反应，但不受LY306155影响。LY303870和LY306740以剂量相关的方式抑制对外周伤害性热刺激的反应，而LY306155仅在较高剂量（2mg/kg或更高）时才有抑制作用。LY303870和LY306740抑制对夹捏刺激的反应。LY306155对夹捏反应缺乏一致的作用。LY303870选择性地抑制对腓浅神经电刺激反应的晚期成分。当测试这三种药物对背角神经元对兴奋性氨基酸N-甲基-D-天冬氨酸的反应时，反应未受影响。这些数据表明，LY303870和LY306740从循环进入脊髓，在那里它们拮抗背角神经元对P物质和伤害性输入的反应。
