Developmental Timing of Neonatal Inflammatory Pain Differentially Alters Adult Dentate Gyrus Plasticity in Male Wistar Rats

Abstract Preterm newborns in neonatal intensive care units are frequently exposed to painful procedures, raising concerns about their neurodevelopmental impact. We investigated whether neonatal inflammatory nociceptive stimulation produces persistent alterations in adult hippocampal function. Male Wistar rat pups received Complete Freund’s Adjuvant in the left hind paw on postnatal day 1 (P1) or 8 (P8). The study focused on long-term potentiation (LTP) and excitability in the adult dentate gyrus, complemented by Morris water-maze performance and hippocampal brain-derived neurotrophic factor (BDNF) as a functional assessment and molecular corroboration, respectively. Hippocampal IL-6, IL-10, and TNF-α were used to assess persistent inflammation, and thermal sensitivity contextualized the model. Electrophysiological effects were layer- and parameter-specific: P1 showed greater normalized slope potentiation in the granule-cell layer but lower normalized EPSP and slope potentiation in the molecular layer than CTR; P8 showed increased population-spike-related measures and lower normalized molecular-layer slope potentiation than CTR. P1 and P8 had shorter escape latencies than CTR on training days 3 and 4, whereas probe-trial performance did not differ. Both stimulated groups showed increased BDNF and reduced thermal sensitivity. No cytokine increases indicative of sustained hippocampal inflammatory activation were detected; at P30, IL-6 and IL-10 were lower in P1 than in age-matched controls. Thus, neonatal inflammatory pain was associated with persistent, developmental-stage-dependent modification of adult dentate gyrus plasticity, supported by concurrent functional and molecular findings without evidence of increased hippocampal IL-6, IL-10, or TNF-α up to P30.