Early life neuroimmune interactions modulate neonatal nociceptive priming

Abstract

Young children perceive nociceptive stimuli and experience pain differently than adults, but the underlying mechanisms that cause these differential effects are unknown. The result of this uncertainty can lead to incomplete pain management for these patients. Further, a vulnerable period occurs during early life whereby aversive stimuli can be biologically encoded possibly through altered neuroimmune and endocrine interactions that influence sensory responsiveness later in life. We evaluated the role of neuroimmune and endocrine interactions in early life, and explored the effects on “neonatal priming.” We assessed pain-like behaviors, sensory neuron response properties with ex vivo electrophysiology, and dorsal root ganglion (DRG) and macrophage specific gene expression under normal and/or genetically altered conditions in both uninjured mice and in animals that experienced surgical hindpaw incisions. We first found that sensory neuron deletion of the receptor for the endocrine signaling molecule growth hormone (GH), induced pain-like behaviors in neonates. Acute peripheral sensitization after incision injury was prevented by local GH treatment, and macrophage ablation of GH receptor also prevented incision-related effects. Macrophages appear to sequester injury-site GH, which releases a tonic inhibition on the sensory neurons and drives primary afferent sensitization. Manipulations in GH signaling or ablating neonatal macrophages was found to be critical for the development of neonatal priming. New ATAC-seq data indicates differences in chromatin accessibility in immature macrophages that may underlie how early life neuroimmune interactions modulate neonatal priming effects. Results demonstrate that the periphery has unique modulators of neonatal nociception that often require distinct immune cell and endocrine signaling activities that influence sensory neuron function. We are currently investigating how altering this process may affect neonatal priming through epigenetic modifications in macrophages. R01NS105715.