Background

Mechanical alloknesis (or innocuous mechanical stimuli–evoked itch) often occurs in dry skin–based disorders such as atopic dermatitis and psoriasis. However, the molecular and cellular mechanisms underlying mechanical alloknesis remain unclear. We recently reported the involvement of CD26 in the regulation of psoriatic itch. This molecule exhibits dipeptidyl peptidase IV (DPPIV) enzyme activity and exerts its biologic effects by processing various substances, including neuropeptides.

Objective

The aim of the present study was to investigate the peripheral mechanisms of mechanical alloknesis by using CD26/DPPIV knockout (CD26KO) mice.

Methods

We applied innocuous mechanical stimuli to CD26KO or wild-type mice. The total number of scratching responses was counted as the alloknesis score. Immunohistochemical and behavioral pharmacologic analyses were then performed to examine the physiologic activities of CD26/DPPIV or endomorphins (EMs), endogenous agonists of μ-opioid receptors.

Results

Mechanical alloknesis was more frequent in CD26KO mice than in wild-type mice. The alloknesis score in CD26KO mice was significantly reduced by the intradermal administration of recombinant DPPIV or naloxone methiodide, a peripheral μ-opioid receptor antagonist, but not by that of mutant DPPIV without enzyme activity. EMs (EM-1 and EM-2), selective ligands for μ-opioid receptors, are substrates for DPPIV. Immunohistochemically, EMs were located in keratinocytes, fibroblasts, and peripheral sensory nerves. Behavioral analyses revealed that EMs preferentially provoked mechanical alloknesis over chemical itch. DPPIV-digested forms of EMs did not induce mechanical alloknesis.

Conclusion

The present results suggest that EMs induce mechanical alloknesis at the periphery under the enzymatic control of CD26/DPPIV.

中文翻译：

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外周内吗啡肽在 CD26/DPPIV 的酶促控制下驱动机械异位

背景

机械性异位运动（或无害的机械刺激诱发的瘙痒）通常发生在基于皮肤干燥的疾病中，例如特应性皮炎和银屑病。然而，机械异位运动的分子和细胞机制仍不清楚。我们最近报道了 CD26 参与调节银屑病瘙痒。该分子表现出二肽基肽酶 IV (DPPIV) 酶活性，并通过处理包括神经肽在内的各种物质发挥其生物学作用。

客观的

本研究的目的是通过使用 CD26/DPPIV 敲除 (CD26KO) 小鼠研究机械异位运动的外围机制。

方法

我们对 CD26KO 或野生型小鼠施加了无害的机械刺激。搔抓反应的总数被计为异动评分。然后进行免疫组织化学和行为药理学分析以检查 CD26/DPPIV 或内吗啡肽 (EM)、μ-阿片受体的内源性激动剂的生理活性。

结果

CD26KO 小鼠比野生型小鼠更频繁地发生机械异位运动。CD26KO 小鼠的异位收缩评分通过皮内给药重组 DPPIV 或纳洛酮甲硫胺（一种外周 μ-阿片受体拮抗剂）显着降低，但没有酶活性的突变型 DPPIV 没有显着降低。EM（EM-1 和 EM-2）是 μ-阿片受体的选择性配体，是 DPPIV 的底物。免疫组织化学显示，EMs 位于角质形成细胞、成纤维细胞和外周感觉神经中。行为分析表明，EMs 比化学瘙痒更能引起机械性异位运动。DPPIV 消化形式的 EM 不会引起机械异位运动。

结论

目前的结果表明，在 CD26/DPPIV 的酶促控制下，EMs 在外周诱导机械异核。