Early life pain alters the response to an immune challenge in adult male and female rats

Infants born prematurely are more likely to be admitted to the Neonatal Intensive Care Unit (NICU) where they experience upwards of 10-18 painful procedures each day, often with no anesthesia or analgesia. Pre-clinical studies have shown that early exposure to pain disrupts CNS development in multiple ways that persist into adulthood, with similar findings observed clinically. The present study explores the effects of neonatal injury on the response to an immune challenge in adulthood. Male and female rats were exposed to a short-term inflammatory insult induced by intraplantar administration of 1% carrageenan (CGN) on the day of birth (P0). In adulthood (P60-P90), rats were implanted with Thermicron iButtons to monitor core body temperature; 14 days later, lipopolysaccharide (LPS) was administered to elicit an immune response. Rats were sacrificed after 24 hours or at their peak fever point and brain tissue collected for immunohistochemical analysis. LPS administration resulted in a significantly greater febrile response in males and females exposed to early life pain compared to controls. Immunohistological analysis revealed sex and treatment differences in Fos labeling in several brain regions, including the PVN. No sex or treatment differences were observed for VGat, VGlut2, or EP3R expression in the MnPO; however, all three increased significantly following LPS administration. Together, these studies are consistent with clinical studies reporting children experiencing unresolved pain during the perinatal period show an increased severity of sickness behavior and altered immune signaling following exposure to a pathogen and will provide a foundation for future studies examining the biological underpinnings.