FABP5: Novel Functions in Pain Modulation - Project Summary Chronic pain is widespread in the adult population and inadequate pain control has a major negative impact on the quality of life of chronic pain sufferers. Many currently available analgesics display modest efficacy and in the case of opioids, addiction liability that has resulted in a dramatic increase in opioid abuse and addiction. Consequently, there is an urgent need to identify novel targets for the development of non-opioid analgesics to treat chronic pain. Our group has previously identified fatty acid binding protein 5 (FABP5) as an intracellular carrier for endocannabinoids and structurally related N-acylethanolamines, whose inhibition augments tissue levels of both lipid classes and produces analgesia. In the periphery, FABP5 inhibition additionally blunts the release of pro-inflammatory and proalgesic mediators, positioning FABP5 as a promising target for the development of analgesics. Accordingly, recently developed FABP5 inhibitors display efficacy in a range of pain models and are rapidly advancing across the preclinical pipeline, with clinical testing scheduled to begin within several years. Despite the therapeutic potential of FABP5 inhibition in treating pain, our understanding of its mechanisms of action remains limited. While the majority of FABP5's effects originate from the modulation of intracellular lipid transport and receptor activation, emerging evidence indicates that subsets of FABPs can be released from distinct cell populations under specific conditions to exert unique biological functions. In this application we test the novel hypothesis that inflammation triggers FABP5 secretion, which is instrumental in delivering proalgesic lipids to nociceptive sensory neurons to maintain hyperalgesia. Conversely, sequestration of extracellular FABP5 produces antinociceptive effects. Mechanistically, we hypothesize that FABP5 binds to and delivers a lipid of the leukotriene family to its receptor, in turn sensitizing the nociceptive channels transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) to sustain pain. Specific Aim 1 tests the hypothesis that extracellular FABP5 modulates inflammatory pain hypersensitivity and will interrogate the mechanisms underlying its cellular secretion. Specific Aim 2 tests the hypothesis that inhibition of extracellular FABP5 or leukotriene signaling blunts inflammatory TRPA1 and TRPV1 sensitization. Specific Aim 3 seeks to characterize the mechanisms underlying leukotriene-mediated TRPA1 sensitization. Successful completion of the outlined aims will establish a novel paradigm linking extracellular FABP5 to pain modulation and will provide a foundation for the development of analgesics targeting FABP5.
