Kovács G L, Acsai L, Tihanyi A, Faludi M, Telegdy G
Pharmacol Biochem Behav. 1983 Mar;18(3):345-9. doi: 10.1016/0091-3057(83)90452-5.
The synethetic dipeptide Z-Prolyl-D-Leucine (Z-Pro-D-Leu) inhibits the development of tolerance to and dependence on morphine in mice. The possible mode of action of the dipeptide was studied by measuring the alpha-MPT-induced disappearance of noradrenaline (NA) and dopamine (DA) either by a spectrofluorimetric assay in major brain areas (lower brainstem, striatum) or by a radioenzymatic assay in specific brain nuclei. For the latter purpose, mouse brain nuclei containing mainly the cell body areas (nucl. tractus solitarii, locus coeruleus, substantia nigra, area tegmentalis ventralis) or some selected terminal projections (nucl. caudatus, nucl. accumbens, gyrus dentatus hippocampi, nucl. raphe dorsalis) of major NA- and DA-containing pathways were selected. In the lower brainstem studied as a whole, the dipeptide did not affect the utilization of either NA or DA. Analysis of the data on the NA utilization in specific brain nuclei, however, revealed that the dipeptide affected NA disappearance in some mesencephalic-limbic nuclei which receive noradrenergic innervation from the dorsal noradrenergic bundle (e.g., nucl. raphe dorsalis, area tegmentalis ventralis, gyrus dentatus). NA utilization in the cell body region of the same pathway (locus coeruleus), however, was not affected by the dipeptide. The dipeptide facilitated DA utilization in the main terminal area of the mesolimbic DA-ergic projection (nucl. accumbens), whereas the same treatment inhibited DA utilization in the main terminal region of the nigro-striatal DA-ergic pathway (nucl. caudatus). The data suggest that localized changes in NA and DA utilization following Z-Pro-D-Leu might be important for peptide-induced changes in morphine tolerance and dependence.
合成二肽Z-脯氨酰-D-亮氨酸（Z-Pro-D-Leu）可抑制小鼠对吗啡耐受性和依赖性的形成。通过在主要脑区（低位脑干、纹状体）采用荧光分光光度法或在特定脑核采用放射酶法测定α-甲基对硫磷诱导的去甲肾上腺素（NA）和多巴胺（DA）的消失情况，研究了该二肽可能的作用方式。为此，选取了主要包含含NA和DA通路的细胞体区域（孤束核、蓝斑核、黑质、腹侧被盖区）或一些选定终末投射（尾状核、伏隔核、海马齿状回、背侧中缝核）的小鼠脑核。在整体研究的低位脑干中，该二肽不影响NA或DA的利用。然而，对特定脑核中NA利用数据的分析表明，该二肽影响了一些接受来自背侧去甲肾上腺素能束的去甲肾上腺素能神经支配的中脑-边缘核（如背侧中缝核、腹侧被盖区、齿状回）中NA的消失。然而，同一通路细胞体区域（蓝斑核）的NA利用不受该二肽影响。该二肽促进了中脑边缘多巴胺能投射主要终末区域（伏隔核）的DA利用，而相同处理则抑制了黑质-纹状体多巴胺能通路主要终末区域（尾状核）的DA利用。这些数据表明，Z-Pro-D-Leu处理后NA和DA利用的局部变化可能对肽诱导的吗啡耐受性和依赖性变化很重要。
