A role for peripheral NAAA-regulated lipid signaling in the control of hyperalgesic priming

Chronic pain is an enormous global health challenge that affects ~50 million adults in the United States alone. Developing safe and effective treatments for this condition is thus of critical importance and requires a deeper understanding of the molecular and cellular mechanisms that lead to pain chronification. It is my career goal to make meaningful contributions toward the solution of this challenging problem. My previous research demonstrated that the transition from acute to chronic pain after paw injury requires a transient suppression of palmitoylethanolamide (PEA) signaling at PPAR-α (peroxisome proliferator-activated receptor-α) in the spinal cord. This event redirects local spinal cord metabolism from mitochondrial respiration toward aerobic glycolysis. This metabolic reprograming (i) generates biomass needed to support synaptic plasticity and (ii) precipitates an energy crisis that contributes to pain chronification. In this K99/R00 application, I propose to test the novel hypothesis that the enzyme N-Acylethanolamine Acid Amidase (NAAA), which deactivates PEA, plays a pivotal role in the emergence of hyperalgesic priming (HP), a model used to study the susceptibility to chronic pain after acute insults. This idea is supported by my recent study indicating that NAAA is expressed at high levels in cell lineages that mediate pain perception and immune reactions and its activity is enhanced by priming stimuli or tissue damage. In addition, NAAA ablation forestall the emergence of HP through a mechanism that requires, at least in part, the restoration of cellular energy balance. These results led the central hypothesis that increased NAAA activity following acute injury might promote the emergence of HP by suppressing intracellular PEA signaling, which is associated with a metabolic shift from respiration, toward aerobic glycolysis. This research program has three pertinent aims to test this hypothesis. In Aim 1, I will utilize a combination of genetic and pharmacological tools to identify the receptor systems involved in NAAA-mediated HP. I hypothesize that NAAA acts by dampening PPAR-α signaling, though other receptors could be involved. In Aim 2, I will identify peripheral cell types involved in NAAA-mediated HP, by answering two questions: (i) does Naaa loss-of-function/gain-of-function in the dorsal root ganglia (DRG) affects the development of HP? and (ii) does priming agents increase NAAA expression in the DRG? Aim 3 will elucidate the molecular mechanism through which NAAA induces HP. I will use transcriptomic, biochemical and pharmacological strategies to probe the role of mitochondrial respiration in NAAA-mediated HP. Collectively, the application will investigate a highly novel and previously unrecognized role of NAAA in HP. The proposal is significant because it addresses an unmet public health need. If successful, it will open new avenues to develop transformative therapies that will be effective in individuals at risk of chronic pain.