Todorov Petar, Assenov Borislav, Angelov Dimo, Dzhambazova Elena, Pechlivanova Daniela
Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria.
Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 23, 1113 Sofia, Bulgaria.
Biomedicines. 2023 Oct 13;11(10):2783. doi: 10.3390/biomedicines11102783.
Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study aimed to reveal a detailed picture of the antinociceptive mechanisms and behavioral effects of V1 and its recently synthesized phosphopeptide analog V2p in rodents using a range of methods. The studied peptides significantly reduced acute (mean V1-9.0, V2p-5.8 vs. controls-54.1 s) and inflammatory (mean V1-57.9 and V2p-53.3 vs. controls-107.6 s) nociceptive pain in the formalin test, as well as carrageenan-induced hyperalgesia (mean V1-184.7 and V2p-107.3 vs. controls-61.8 g) in the paw pressure test. These effects are mediated by activation of opioid receptors with a predominance of kappa in V1 antinociception and by delta, kappa, and mu receptors in V2p-induced antinociception. Both peptides did not change the levels of TNF-alpha and IL-1-beta in blood serum. V1 induces depression-like behavior, and V2p shows a tendency toward anxiolysis and short-term impairment of motor coordination without affecting exploratory behavior. The results characterize valorphin and its derivative as promising analgesics that exert their effects both centrally and peripherally, without causing severe behavioral changes in experimental animals. These encouraging data are a foundation for future studies focusing on the effects of hemorphins after long-term treatment.
Valorphin（V1）是一种天然存在的源自血红蛋白的肽，已发现它对阿片受体具有亲和力，并表现出抗伤害感受和抗惊厥活性。其一些含有氨基膦酸酯部分的合成类似物显示出结构依赖性的强效抗伤害感受作用。本研究旨在使用一系列方法揭示V1及其最近合成的磷酸肽类似物V2p在啮齿动物中的抗伤害感受机制和行为效应的详细情况。在福尔马林试验中，所研究的肽显著降低了急性（平均V1为9.0、V2p为5.8，而对照组为54.1秒）和炎性（平均V1为57.9、V2p为53.3，而对照组为107.6秒）伤害感受性疼痛，以及在爪压力试验中角叉菜胶诱导的痛觉过敏（平均V1为184.7、V2p为107.3，而对照组为61.8克）。这些效应是通过阿片受体的激活介导的，在V1的抗伤害感受中以κ受体为主，而在V2p诱导的抗伤害感受中则通过δ、κ和μ受体。两种肽均未改变血清中TNF-α和IL-1-β的水平。V1诱导抑郁样行为，而V2p表现出抗焦虑倾向以及运动协调的短期损害，而不影响探索行为。结果表明valorphin及其衍生物是有前景的镇痛药，它们在中枢和外周均发挥作用，且不会在实验动物中引起严重的行为变化。这些令人鼓舞的数据为未来关注长期治疗后血啡肽效应的研究奠定了基础。
