FAAH-regulated endocannabinoid signaling controls nociception in acute pancreatitis

PROJECT SUMMARY/ABSTRACT Acute pancreatitis (AP) is a prevalent gastrointestinal disorder characterized by severe abdominal pain, leading to substantial hospital admissions worldwide. The current reliance on opioid analgesics for pain management in AP introduces risks such as abuse, dependence, and possibly exacerbated disease outcomes. Emerging evidence suggests that the endogenous lipid-signaling molecules anandamide and palmitoylethanolamide (PEA), which produce analgesia through non-opioid mechanisms, could offer a promising alternative for pain relief. However, their therapeutic potential is limited by rapid breakdown via the enzyme fatty acid amide hydrolase (FAAH). This project seeks to explore FAAH-regulated lipid signaling as a novel, opiate-sparing therapeutic target for managing AP pain. Preliminary studies have demonstrated that inhibiting FAAH leads to significant antinociceptive effects in animal models of AP, supporting the hypothesis that FAAH plays a crucial role in modulating AP pain through the degradation of anandamide and PEA. This research project is structured around three specific aims: First, to identify the receptor systems, including CB1 cannabinoid receptors, PPARα, and others, that mediate the analgesic effects of FAAH inhibition in AP. Second, to assess changes in FAAH expression and activity, alongside levels of anandamide and PEA, providing insight into the regulatory mechanisms at play during AP. A subsequent aim will delve into the cellular substrates mediating analgesia from FAAH inhibition, employing state-of-the-art techniques such as snRNAseq and CyTOF to profile cell populations and their transcriptional landscapes. The final aim addresses whether anandamide and PEA exert redundant or synergistic analgesic effects in AP. By revealing the intricate mechanisms of FAAH-regulated signaling and its impact on pain relief, this project stands to significantly advance our understanding of non-opioid analgesic pathways in AP. Success in these aims could lay the groundwork for the development of novel, effective, and safer pain management strategies for AP, reducing opioid reliance and its associated risks.