Emmers R, Tamir H, Wilchek M
Exp Neurol. 1987 Jun;96(3):501-15. doi: 10.1016/0014-4886(87)90214-7.
The antinociceptive properties of a new synthetic dipeptide (N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, or 5-HTP-DP-hex) were studied in rats by an electrophysiological method. After an i.p. injection of alpha-chloralose and urethane, the animals were prepared for stereotaxic approach to the nucleus ventralis posterolateralis of the thalamus. With tungsten microelectrodes, individual nociceptive neurons in the nucleus were identified by the sequence of spikes emitted in response to single-pulse stimulation of the sciatic nerve. In addition to the usual short-latency spikes, a nociceptive neuron fired late spikes at regular intervals within 500 ms following each stimulus. When the spikes were accumulated in poststimulus time histograms, the short-latency spikes compiled an intensity-related (I) peak. The late spikes formed modality-related (M) peaks with spacing characteristic of nociception. Intracarotid infusion of 5-HTP-DP-hex (1 mg/kg) elevated the delayed portion of the I peak and the first M peak. This effect was followed in 25 min by suppression of all M peaks. The control record could be reinstated at any time by 5-hydroxytryptophan (3.5 mg/kg), or by natural recovery in 2.5 h. Responses evoked from a thalamic nociceptive neuron by single-pulse stimulation of the spinothalamic tract were modified by 5-HTP-DP-hex in a similar manner, except that no elevation of the activity peaks was observed. As shown previously, elevation of the delayed I peak and M1 indicated an increased input of A-delta and C fibers, respectively. The increased input lowers the response threshold and may represent hyperalgesia. Suppression of the M peaks may result from altered function of the positive feedback loop in the nociceptive system at the thalamic level, and may represent analgesia. Naloxone, methysergide, as well as ketanserin had no significant effect on the response histograms. These findings suggested that 5-HTP-DP-hex, a known serotonin receptor antagonist, targeted its action on very specific receptors, and thus interfered with particular synaptic activity within the spinal cord and on the thalamic level.
采用电生理方法在大鼠中研究了一种新型合成二肽（N-己酰基-5-羟色氨酰-5-羟色氨酸酰胺，即5-HTP-DP-己）的抗伤害感受特性。腹腔注射α-氯醛糖和乌拉坦后，对动物进行立体定位，以接近丘脑腹后外侧核。使用钨微电极，通过对坐骨神经单脉冲刺激所发射的尖峰序列来识别该核中的单个伤害感受神经元。除了通常的短潜伏期尖峰外，一个伤害感受神经元在每次刺激后的500毫秒内以规则间隔发射晚期尖峰。当尖峰累积在刺激后时间直方图中时，短潜伏期尖峰构成强度相关（I）峰。晚期尖峰形成与模式相关（M）峰，具有伤害感受的间隔特征。颈内注入5-HTP-DP-己（1毫克/千克）可提高I峰的延迟部分和第一个M峰。25分钟后，所有M峰受到抑制。通过5-羟色氨酸（3.5毫克/千克）或2.5小时后的自然恢复，可随时恢复对照记录。5-HTP-DP-己以类似方式改变了由单脉冲刺激脊髓丘脑束从丘脑伤害感受神经元诱发的反应，但未观察到活动峰的升高。如先前所示，延迟I峰和M1峰的升高分别表明A-δ纤维和C纤维的输入增加。输入增加会降低反应阈值，可能代表痛觉过敏。M峰的抑制可能是由于丘脑水平伤害感受系统中正反馈回路功能改变所致，可能代表镇痛作用。纳洛酮、麦角新碱以及酮色林对反应直方图无显著影响。这些发现表明，作为已知的5-羟色胺受体拮抗剂，5-HTP-DP-己将其作用靶向非常特定的受体，从而干扰脊髓内和丘脑水平的特定突触活动。
