Mast cell stabilizers as novel analgesics in the therapy of acute and chronic pancreatitis

急性和慢性胰腺炎与严重的腹痛有关，而腹痛往往对有效的止痛治疗无效。我们以前可以证明，慢性胰腺炎的痛感程度与胰腺内神经中肥大细胞的数量有关。为此，在最初的项目中，我们假设在肥大细胞稳定剂的帮助下阻断肥大细胞可以对胰腺炎患者起到显著的止痛作用。总之，我们能够证明肥大细胞稳定剂在实验性慢性胰腺炎中起到了镇痛作用。由于目前从伦理学的角度来看，单独使用肥大细胞稳定剂作为止痛剂是不合理的，我们将肥大细胞稳定剂(作为“辅助止痛剂”)与已建立的止痛剂(安非他唑)联合应用在实验性急性和慢性胰腺炎的第一次后续应用中纳入了镇痛效果。在这里，无论是急性胰腺炎还是慢性胰腺炎，动物的疼痛几乎完全消退，导致了“无痛性胰腺炎”。我们对肥大细胞和神经元共同培养的分泌组和转录组分析表明，这些药物导致肥大细胞特异性地增加抗炎细胞因子IL10的释放，减少促炎细胞因子Fractalkine(CX3CL1)的表达。因此，我们的结果提示，肥大细胞稳定剂对慢性和急性肥大细胞的镇痛作用可能是由于对激活的肥大细胞中细胞因子活性的有利调节。在目前的第二次后续拨款申请中，我们想机械地继续这一观察。为此，我们将首先使用转基因肥大细胞和肥大细胞或神经元特异性调节IL10信号通路的小鼠，并将研究这些小鼠在实验性急性和慢性胰腺炎期间的痛觉感受。在最后的部分中，我们将把慢性胰腺炎患者的肥大细胞激活情况与他们的疼痛感知和生活质量相关联，以弥合我们的发现的临床前好处与其临床应用之间的差距。因此，这项后续研究蕴含着将肥大细胞稳定剂用于内脏疼痛综合征的药物再利用的潜力。

Acute and chronic pancreatitis are associated with severe abdominal pain, which is frequently refractory to potent analgesic therapy. We could previously show that the extent of pain sensation in chronic pancreatitis is related to the amount of mast cells that infiltrate the intrapancreatic nerves. For this reason, in the initial project we hypothesized that the blockade of mast cells with the help of mast cell stabilizers can contribute to significant analgesia in pancreatitis patients. In harmony, we were able to show that mast cell stabilizers exerted an analgesic effect in experimental chronic pancreatitis. Since the administration of mast cell stabilizers alone as analgesics is currently not justifiable from an ethical point of view, we have included the analgesic effect of a combined administration of mast cell stabilizers (as "co-analgesics") in the first follow-up application together with an established analgesic (metamizole) in experimental acute and chronic pancreatitis. Here, there was an almost complete regression of the pain in the animals in both acute and chronic pancreatitis, resulting in a “painless pancreatitis”. Our secretome and transcriptome analysis in co-cultures of mast cells and neurons exposed to these drugs showed that these drugs lead to a specific, increased release of the anti-inflammatory cytokine IL10, and to a reduced expression of the pro- inflammatory cytokine fractalkine (CX3CL1) in the mast cells. Our results, therefore, suggest that the analgesic effect of mast cell stabilizers in chronic and acute might be due to a favorable modulation of the cytokine activity in the activated mast cells. In the present, second follow-up grant application, we would like to pursue this observation mechanistically. For this purpose, we will first use genetically modified mast cells and mice with mast cell- or neuron-specific modulation of the IL10 signaling pathway and will investigate the pain perception of these mice during experimental acute and chronic pancreatitis. In the final part, we will correlate the mast cell activation profile of patients with chronic pancreatitis with their pain perception and quality of life for bridging the gap between the preclinical benefits of our discoveries and their clinical application. This follow-up study thus harbors the potential for a drug repurposing in the use of mast cell stabilizers in visceral pain syndromes.