Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain.

TitleTempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain.
Publication TypeJournal Article
Year of Publication2012
AuthorsLochhead JJ, McCaffrey G, Sanchez-Covarrubias L, Finch JD, DeMarco KM, Quigley CE, Davis TP, Ronaldson PT
JournalAm J Physiol Heart Circ Physiol
Date Published2012 Feb 01
KeywordsAcute Disease, Aldehydes, Analgesics, Opioid, Animals, Antioxidants, Blood-Brain Barrier, Capillary Permeability, Carbon Radioisotopes, Codeine, Cyclic N-Oxides, Cysteine Proteinase Inhibitors, Hyperalgesia, Male, Membrane Proteins, Neuralgia, Neuritis, Occludin, Oxidative Stress, Rats, Rats, Sprague-Dawley, Spin Labels, Sucrose, Tight Junctions, Tyrosine, Xenobiotics

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.

Alternate JournalAm. J. Physiol. Heart Circ. Physiol.
PubMed ID22081706
PubMed Central IDPMC3353792
Grant ListR01 DA011271 / DA / NIDA NIH HHS / United States
R01 NS042652 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Jeffrey J. Lochhead, PhD
Patrick T Ronaldson, PhD