Early life programming of pain: Neuroimmune to endocrine symphony

Chronic pain constitutes a major challenge for clinical and experimental scientists. This is due to the failure of current drugs targeting neurons only. We now know that pain can result from the interaction between the immune, endocrine, and nervous systems. Neonatal LPS exposure can alter neuroendocrine responses in adult rats. How neonatal LPS exposure program future pain responses is unknown. Rat pups were exposed to either LPS or saline (0.05 mg/kg, IP) on postnatal days (PND) 3 and 5. At PND 22 and PND80-97, rats received a hind paw injection of formalin. One hour later, blood and hippocampus were collected to measure circulating IL-1 β , CORT, and hippocampal IL-1 β . Paw tissue was collected to assess mast cell degree of degranulation. Additionally, 1.5 h following behavioral scoring brains were immunolabeled for Fos in the PAG. LPS-treated rats exhibited hyperalgesia at PND 22 ( p 0.1 ) and PND 80-97 ( p 0.5 ). The LPS-induced hyperalgesia observed at PND 22 coincides with enhanced circulating IL-1 β and mast cell degranulation, increased CORT as well as decreased Fos-labeling in the PAG. At PND80-97, LPS-treated rats had increased hippocampal IL-1 β and enhanced Fos-labeling in the PAG. No changes were observed in peripheral IL-1 β or CORT. Together, these data demonstrate the importance of the neonatal microbial environment in programming future inflammatory pain responses via developmentally regulated actions on the immune, endocrine, and supraspinal neural pathways.