Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability, altered tight junction protein expression and the delivery of opioid analgesics to the brain. What remains unknown is which pathways and mediators during peripheral inflammation affect BBB function and structure. The current study investigated effects of -carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of pro-inflammatory cytokines and microglial activation in the brain to elucidate possible pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels following CIP using RT-PCR and Western blot analyses, screened inflammatory cytokines during the time course of inflammation, assessed white blood cell counts, and probed for BBB and CNS stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression following CIP with no change in circulating levels of several pro-inflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal/parietal cortices, which directly correlated with increased expression of activated microglia. Findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic pro-inflammatory mediators played no apparent role in the early response (1-6 h); however, brain region specific increases in microglial activation suggest a potential for a central-mediated response.