The objective of this study was to test whether postnatal chronic inflammation resulted in altered reactivity to pain later in life when reexposed to the same inflammatory agent and whether this alteration correlated with brain-region-specific patterns of N-methyl-D-aspartate (NMDA) receptor subtype gene expression. Neonatal mouse pups received a single injection of complete Freund's adjuvant (CFA) or saline into the left hind paw on postnatal day 1 or 14. At 12 weeks of age, both neonatal CFA- and saline-treated animals received a unilateral injection of CFA in the left hind paw. Adult behavioral responsiveness of the left paw to a radiant heat source was determined in mice treated neonatally with saline or CFA before and after receiving CFA as adults. Twenty-four hours later, brains were dissected and NMDA receptor subunit gene expression was determined in four different brain areas by using an RNase protection assay. The results indicated that NMDA receptor subtype gene expression in adult mice exposed to persistent neonatal peripheral inflammation was brain region specific and that NMDA gene expression and pain reactivity differed according to the day of neonatal CFA exposure. Similarly, adult behavioral responsiveness to a noxious radiant heat source differed according to the age of neonatal exposure to CFA. The data suggest a possible molecular basis for the hypothesis that chronic persistent inflammation experienced early during development may permanently alter the future behavior and the sensitivity to pain later in life, especially in response to subsequent or recurrent inflammatory events.