Our laboratory has shown that λ-
carrageenan-induced peripheral inflammatory
pain (CIP) can alter tight junction (TJ)
protein expression and/or assembly leading to changes in blood-brain barrier
xenobiotic permeability. However, the role of
reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e.,
superoxide) are known to cause cellular damage in response to
pain/
inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain barrier (BBB) in CIP rats. During CIP, increased staining of nitrosylated
proteins was detected in hind paw tissue and enhanced presence of
protein adducts containing
3-nitrotyrosine occurred at two molecular weights (i.e., 85 and 44 kDa) in brain microvessels.
Tempol, a pharmacological ROS scavenger, attenuated formation of 3-nitrotyrosine-containing
proteins in both the hind paw and in brain microvessels when administered 10 min before footpad injection of λ-
carrageenan. Similarly, CIP increased 4-hydroxynoneal staining in brain microvessels and this effect was reduced by
tempol. Brain permeability to [(14)C]
sucrose and [(3)H]
codeine was increased, and oligomeric assemblies of
occludin, a critical TJ
protein, were altered after 3 h CIP.
Tempol attenuated both [(14)C]
sucrose and [(3)H]
codeine brain uptake as well as protected
occludin oligomers from disruption in CIP animals, suggesting that ROS production/oxidative stress is involved in modulating BBB functional integrity during
pain/
inflammation. Interestingly,
tempol administration reduced
codeine analgesia in CIP animals, indicating that oxidative stress during
pain/
inflammation may affect
opioid delivery to the brain and subsequent efficacy. Taken together, our data show for the first time that ROS pharmacological scavenging is a viable approach for maintaining BBB integrity and controlling central nervous system drug delivery during acute inflammatory
pain.