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Early life physiological stressors have been implicated in the onset of psychopathology in adulthood. In preclinical models, the neonatal bacterial immune challenge, lipopolysaccharide (LPS), has been shown to alter anxiety-like behaviour, neuroendocrine function and behavioural pain responses in adulthood. Interestingly, recent evidence suggests a role for the lateral hypothalamic peptide orexin in stress, arousal and nociceptive processing. How a neonatal LPS exposure affects the reactivity of the orexin system to formalin-induced inflammatory pain in adulthood remains to be determined. Male Wistar rat pups (n = 12) were exposed to either LPS or saline (0.05 mg/kg, IP) on postnatal days (PND) 3 and 5. On PND 82–97, all rats were exposed to a subcutaneous hindpaw injection of 2.25% formalin (50 μL). 1.5 h following behavioural testing, animals were perfused and brains processed for Fos-protein and orexin immunohistochemistry. LPS-treated rats exhibited increased flinching but not licking responses in adulthood compared to saline controls (p

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.