[Leu5]-Enkephalin is an endogenous δ-opioid receptor agonist that modulates pain perception and emotion by binding to opioid receptors[1,2]. [Leu5]-Enkephalin is commonly used in the development of novel analgesic drugs and in the treatment and research of neurodegenerative diseases[3,4].
In vitro, [Leu5]-Enkephalin (5-50μM) treatment of human immortalized keratinocyte HaCaT cells for 21h significantly promoted cell migration and scratch wound closure. [Leu5]-Enkephalin (20μM) treatment of HaCaT cells for 24h significantly up-regulated the gene expression levels of matrix metalloproteinases MMP-2 and MMP-9[5]. [Leu5]-Enkephalin (50μg/mL) treatment of the scallop Chlamys farreri haemolymph for 1h significantly increased catalase (CAT) activity and glutathione (GSH) levels in both haemocyte lysate supernatant (intracellular) and plasma supernatant (extracellular)[6].
In vivo, [Leu5]-Enkephalin (1mg/kg) administered via subcutaneous injection in a mouse model of colorectal distension-induced visceral pain significantly reduced the visceromotor response elicited by 60mmHg pressure stimulation[7]. [Leu5]-Enkephalin (1fM; 5μL) co-administered intrathecally with the peptidase inhibitors phosphoramidon (2nM) and bestatin (0.25nM) in ddY-strain mice induced characteristic nociceptive behaviors (scratching, biting, licking), which peaked at 10-15min and gradually subsided within 30min[8].
References:
[1] HOHENWARTER L, PUIL E, ROUHOLLAHI E, et al. A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects[J]. Molecular Pharmaceutics, 2024, 21(2): 688-703.
[2] CULLEN J M, CASCELLA M. Physiology, enkephalin[J]. 2020.
[3] MIURA M, YOSHIKAWA M, WATANABE M, et al. Increase in antinociceptive effect of [leu5] enkephalin after intrathecal administration of mixture of three peptidase inhibitors[J]. Tokai Journal of Experimental and Clinical Medicine, 2013, 38(2): 62-70.
[4] VISWANADHAM K K D R, BÖTTGER R, HOHENWARTER L, et al. An effective and safe enkephalin analog for antinociception[J]. Pharmaceutics, 2021, 13(7): 927.
[5] YANG D J, LEE K S, KO C M, et al. Leucine-enkephalin promotes wound repair through the regulation of hemidesmosome dynamics and matrix metalloprotease[J]. Peptides, 2016, 76: 57-64.
[6] LIU D. Effects of Leucine-enkephalin on catalase activity and glutathione level in haemolymph of the scallop Chlamys farreri[J]. International Journal of Peptide Research and Therapeutics, 2008, 14(1): 16-20.
[7] FABISIAK A, SOBOCIŃSKA M, KAMYSZ E, et al. Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof-of-concept[J]. Chemical Biology & Drug Design, 2018, 92(1): 1387-1392.
[8] KOMATSU T, KATSUYAMA S, MIZOGUCHI H, et al. Spinal ERK2 activation through δ₂-opioid receptors contributes to nociceptive behavior induced by intrathecal injection of leucine-enkephalin[J]. Peptides, 2014, 54: 131-139.
[Leu5]-Enkephalin是一种通过与阿片受体结合以调节疼痛感知和情绪的内源性δ阿片受体激动剂[1,2]。[Leu5]-Enkephalin通常用于新型镇痛药物的开发及神经退行性疾病的治疗和研究[3,4]。
在体外，[Leu5]-Enkephalin（5-50μM）处理人永生化角质形成HaCaT细胞21h，能显著促进细胞的迁移和划痕伤口的闭合。[Leu5]-Enkephalin（20μM）处理HaCaT细胞24h，能显著上调基质金属蛋白酶MMP-2和MMP-9的基因表达水平[5]。[Leu5]-Enkephalin（50μg/mL）处理扇贝Chlamys farreri血淋巴1h，能显著提升血淋巴细胞裂解上清液（细胞内）和血浆上清液（细胞外）中过氧化氢酶（CAT）的活性和谷胱甘肽（GSH）的水平[6]。
在体内，[Leu5]-Enkephalin（1mg/kg）通过皮下注射处理结直肠扩张诱导的内脏疼痛小鼠模型，显著降低了由60mmHg压力刺激引起的内脏运动反应[7]。[Leu5]-Enkephalin（1fM; 5μL）与肽酶抑制剂phosphoramidon（2nM）和bestatin（0.25nM）联合鞘内注射ddY品系小鼠，可诱导典型的伤害性行为（抓挠、咬、舔），该行为在10-15min达到峰值，并在30min内逐渐消失[8]。