Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain.
Previous studies showed that peripheral inflammatory pain increased blood-brain barrier (BBB) permeability and 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 lambda-carrageenan-induced inflammatory pain (CIP) on BBB expression of ICAM-1. We also examined the systemic contribution of a number of proinflammatory cytokines and microglial activation in the brain to elucidate pathways involved in BBB disruption during CIP. We investigated ICAM-1 RNA and protein expression levels in isolated rat brain microvessels after 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 central nervous system stimulation and leukocyte transmigration using immunohistochemistry and flow cytometry. Results showed an early increase in ICAM-1 RNA and protein expression after CIP with no change in circulating levels of several proinflammatory cytokines. Changes in ICAM-1 protein expression were noted at 48 h. Immunohistochemistry showed that the induction of ICAM-1 was region specific with increased expression noted in the thalamus and frontal and parietal cortices, which directly correlated with increased expression of activated microglia. The findings of the present study were that CIP induces increased ICAM-1 mRNA and protein expression at the BBB and that systemic proinflammatory mediators play 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.
Huber
J D
JD
Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, USA.
Campos
C R
CR
Mark
K S
KS
Davis
T P
TP
D000818:Animals; D001772:Blood Cell Count; D001808:Blood Vessels / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D002351:Carrageenan; D016207:Cytokines / Q000097:blood; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007150:Immunohistochemistry; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology; D008833:Microcirculation; D017628:Microglia; D020556:Neutrophil Infiltration; D010146:Pain / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D002351:Carrageenan