Electrical stimulation models and mediators conveying pruritus in allergic contact dermatitis and urticaria patients

过敏性接触性皮炎和荨麻疹患者瘙痒的电刺激模型和介质

• 批准号: 399486728
• 负责人: Professor Dr. Martin Metz, Ph.D.
• 金额: --
• 依托单位: Klinik für Anästhesie, Operative Intensivmedizin und Schmerzmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/399486728?language=en
• 关键词: Electrical; stimulation; models; mediators; conveying

Slowly depolarizing electrical stimuli induce pain in healthy volunteers but pruritus in about 30% of patients suffering chronic itch. Notably, electrically induced pain and itch ameliorates with ongoing stimulation (habituation). In the present project proposal, we aim to develop and establish an electrical stimulation paradigm that continuously evokes itch without habituation in patients with chronic pruritus, enabling neurophysiological basic research in various itch entity. At first, the stimulation paradigm will be developed in healthy human subjects, validated in single nerve fiber recordings in the pig in vivo, and after establishment of the protocol applied in patients with allergic contact eczema and chronic spontaneous urticarial. We will deliver the stimulation protocol to all projects of the research unit investigating chronic inflammatory, systemic and neuropathic pruritus. The duration and intensity of electrically evoked itch will be correlated with structural parameters of the skin, i.e. the intra-epidermal nerve fiber density and their neuronal branching pattern. These parameters will be identified in skin punch biopsies obtained from lesional and non-lesional skin of patients with contact eczema and urticaria, respectively. In addition, interstitial fluid will be collected by intradermal microdialysis from these skin sites and analyzed for interleukin-31, a cytokine that is associated with chronic pruritus. The dialysate of contact allergy patients will be analyzed for non-cellular microRNA. Free circulating microRNA was identified as biomarker in various chronic painful and pruritic conditions. The analyzed microRNA in lesional and non-lesional skin of contact allergy patients will be compared to healthy control subjects and with data from the literature described for atopic eczema and psoriasis. In chronic urticaria patients, we will explore the sensitization level of skin mast cells. Mast cells express the mas-related G protein-coupled receptor X2 (MRGPRX2) and have been attributed to play a pivotal role in the pathology of urticaria. In affected and non-affected skin of chronic spontaneous and induced urticarial skin we will deliver with pinprick the MRGPRX2 agonisten ciprofloxacin and measure by means of intradermal microdialysis the release of tryptase and histamine. A differential MRGPRX2-induced release of these mediators would indicate a sensitized activation of skin mast cells and provide new therapeutic approaches in the treatment of urticaria.

缓慢去极化电刺激在健康志愿者中引起疼痛，但在约30%的慢性瘙痒患者中引起瘙痒。值得注意的是，电诱导的疼痛和瘙痒随着持续刺激（习惯化）而改善。在本项目提案中，我们的目标是开发和建立一种电刺激范式，在慢性瘙痒症患者中持续引起瘙痒而不习惯，从而实现各种瘙痒实体的神经生理学基础研究。首先，将在健康人类受试者中开发刺激范例，在猪体内的单神经纤维记录中进行验证，并在建立应用于过敏性接触性湿疹和慢性自发性荨麻疹患者的方案之后。我们将为研究慢性炎症性、全身性和神经性瘙痒症的研究单位的所有项目提供刺激方案。电诱发瘙痒的持续时间和强度将与皮肤的结构参数相关，即表皮内神经纤维密度及其神经元分支模式。这些参数将分别从接触性湿疹和荨麻疹患者的病灶和非病灶皮肤获得的皮肤穿刺活检中确定。此外，将通过皮内微透析从这些皮肤部位收集间质液，并分析白细胞介素-31（一种与慢性瘙痒相关的细胞因子）。将对接触性过敏患者的透析液进行非细胞microRNA分析。游离循环microRNA被鉴定为各种慢性疼痛和关节炎病症的生物标志物。将接触性变态反应患者的损伤和非损伤皮肤中分析的microRNA与健康对照受试者进行比较，并与来自特应性湿疹和银屑病文献的数据进行比较。在慢性荨麻疹患者中，我们将探讨皮肤肥大细胞的致敏水平。肥大细胞表达mas相关的G蛋白偶联受体X2（MRGPRX 2），并已被认为在荨麻疹的病理学中发挥关键作用。在慢性自发性和诱导性荨麻疹皮肤的受影响和未受影响的皮肤中，我们将用针刺递送MRGPRX 2激动剂环丙沙星，并通过皮内微透析测量类胰蛋白酶和组胺的释放。不同的MRGPRX 2诱导的这些介质的释放将表明皮肤肥大细胞的致敏活化，并为荨麻疹的治疗提供新的治疗方法。