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

• Applicant: Professor Dr. Ihsan Ekin Demir
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325247933

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.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Stephan Schorn