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 early life injury, which influences outcomes related to nociception following subsequent injury later in life (neonatal nociceptive priming). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling. The p75 neurotrophic factor receptor (NTR) was an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This pain memory was long lasting in females and could be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury.