Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming.

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"). The underpinnings of this phenomenon are largely unknown, although macrophages can be epigenetically trained by injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling of peripheral macrophages. The p75 neurotrophic factor receptor (NTR) was observed to be an important effector in regulating neonatal nociceptive priming. p75NTR modulates the inflammatory profile and responses of rodent and human macrophages. This "pain memory" was able to be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute post-surgical pain may transition to chronic pain in children.