Targeting sphingosine-1-phosphate receptor 1 alleviates neuropathic pain associated with pancreatic ductal adenocarcinoma in mice and inhibits tumor progression

BACKGROUND: Pancreatic neuropathy occurs during the development of pancreatic ductal adenocarcinoma (PDAC), with changes correlating to pancreatic neuropathic pain and increased expression of nociceptive genes in sensory ganglia. Emerging evidence suggests that sphingosine-1-phosphate receptor 1 (S1PR1) plays critical roles in the onset and maintenance of pain. However, whether S1PR1 in sensory ganglia contributes to PDAC-associated neuropathic pain remains unclear. METHODS: We collected histopathological sections and pain-related data from patients who underwent surgical resection and were pathologically confirmed as having PDAC. S1PR1 levels in intrapancreatic nerves were measured using immunohistochemistry. A mouse model of PDAC-associated pain was established in C57BL/6J mice via orthotopic transplantation of MT5 cells. Pain behaviors were evaluated through abdominal mechanical hyperalgesia, hunch score, and open-field tests. The changes and subcellular localization of S1PR1 in dorsal root ganglia (DRGs) were observed. Subsequently, the S1PR1 antagonists W146 and FTY720 were administered to investigate the underlying molecular mechanisms. We further assessed the analgesic efficacy and its impact on tumor progression of the S1PR1 antagonist FTY720. RESULTS: S1PR1 levels in nerves from PDAC patients experiencing cancer-associated pain were significantly higher compared to those without such pain. In the DRGs of a PDAC mouse model, S1PR1 expression was upregulated and colocalized with neurons and satellite glial cells. Intrathecal injection of S1PR1 antagonists W146 and FTY720 effectively alleviated PDAC-induced neuropathic pain hypersensitivity and suppressed the upregulation of transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP). Additionally, FTY720 alleviated pancreatic cancer-related neuropathic pain and demonstrated partial anti-tumor effects. CONCLUSIONS: Our findings indicate that S1PR1 in DRGs plays a pivotal role in PDAC-associated neuropathic pain. Inhibition of S1PR1 signaling may alleviate PDAC-related neuropathic pain, and targeting S1PR1 represents a promising strategy for adjuvant management of pancreatic cancer-related pain.