Thursday, December 26, 2024
12/26/2024
ABSTRACT: Approximately 15-20% of children experience persistent or chronic pain. However, compared to adults, we know relatively little about the mechanisms of pediatric pain development. A basic understanding of nociceptive processing in the immature nervous system is therefore crucial in order to develop more appropriate treatments for pain in children. The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to effects of early life injury which can influence outcomes related to nociception following subsequent injury later in life (i.e. “neonatal nociceptive priming”). We have found that macrophages are a key player in both early life nociception and neonatal nociceptive priming responses after incision injuries. Macrophages were found to retain an epigeneetically driven memory of early life injury that leads to a more pro-inflammatory state such that re-injury causes a prolonged behavioral and physiological responses in the peripheral nervous system. Observed changes in the PNS that underlie neonatal nociceptive priming are blocked by genetic targeting of the nerve growth factor (NGF) receptor, p75, in macrophages, one of the key factors found to be part of the epigenetic memory. New pilot data suggests that mast cells (MCs) may be the source of NGF that sustains the pro-inflammatory state created by the epigenetic memory in macrophages. In addition, sensory neurons also appear to generate an epigenetically driven memory that contributes to the pro-inflammatory environment in the muscles after injury leading to prolonged hypersensitivity. The main goal of this proposal is to determine how the epigenetic modifications in this novel neuro-immune circuit regulates neonatal nociceptive priming. Specific Aim 1 will use our novel ex vivo somatosensory recording preparations and pain-like behavioral assays along with cell specific transgenic approaches to determine the additional epigenetically modified factors in macrophages (e.g. parvalbumin) that regulate neonatal nociceptive priming. Specific Aim 2 will test whether knockdown of neuronally produced cytokines (e.g. interleukin 34) modulates neonatal nociceptive priming using similar approaches with nerve targeted gene knockdown strategies. Finally, Specific Aim 3 will use behavioral analyses and/or ex vivo recording to determine the influence of MCs and MC produced NGF in neonatally incised mice on the prolonged effects to subsequent adolescent incision. These aims will be complemented by calcium imaging analysis of human iPSC derived sensory neurons treated with media from macrophages or MCs to enhance translational potetinal of these studies. These experiments will allow a better understanding of the unique mechanisms by which neuroimmune signaling contributes to neonatal nociceptive priming. These studies will facilitate understanding of the transition from acute to chronic pediatric post-surgical pain, and will allow us to determine the utility of targeting immune cell or sensory neuron memories as a pain therapy for children.
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