Pain afflicts more than 85 million people in the United States each year, causing tremendous suffering and costing billions of dollars in medical treatments and lost productivity. Pain-induced blood-brain barrier (BBB) dysfunction significantly alters transport into the brain of clinically relevant drugs used to treat pain. Moreover, BBB dysfunction initiates and/or exacerbates numerous central nervous system (CNS) and non-CNS diseases and pathologies associated with pain and/or inflammation, including Alzheimer's disease, ischemic stroke, arthritis, diabetes, multiple sclerosis and atherosclerosis. Unfortunately, most research on the distribution of neuropharmaceuticals to the CNS has been performed using naive, healthy animals not suffering from pain and/or inflammation. Studies from our laboratory show that peripheral inflammatory pain induced by ?-carrageenan, formalin or complete Freund's adjuvant, increases paracellular BBB permeability, alters multi-drug resistant (MDR) P-glycoprotein (P-gp) expression and brain uptake of opiates used clinically to treat pain. Additionally, we find that peripheral inflammatory pain alters expression and localization of the key Tight Junction (TJ) proteins occludin, claudin-3, claudin-5 and zona occludens 1 (ZO-1) which are critically important in restricting BBB paracellular transport. All categories of pain (acute, subchronic and chronic) can be initiated by a painful stimulus or inflamagen that elicits both a peripheral innate immune response and a CNS-mediated response. The peripheral innate immune response involves the rapid production and local release of inflammatory mediators at the site of injury of inflammation. The CNS response to peripheral inflammation pain involves glia activation, de novo synthesis of proinflammatory cytokines and growth factors, and exaggerated pain transmission (hyperalgesia). The overall goal of this proposal is to provide a detailed understanding of how peripheral pain and inflammation cause the changes in BBB structure and function that lead to altered delivery to the brain of important pharmaceuticals used to treat pain and CNS disease. Our hypothesis is that both the peripheral innate immune response and the CNS-mediated response to peripheral inflammatory pain elicit changes in the expression and intracellular trafficking of key TJ and MDR (P-gp) proteins in microvascular endothelial cells at the BBB, and that these changes critically affect BBB cell signaling, paracellular permeability and efflux transport.
The aims of this grant will be investigated using a combination of biochemical, molecular, pharmacological and in vivo methods established and working in our laboratory. This proposal will elucidate underlying mechanism of BBB changes induced by pain and inflammation, and will facilitate discovery of novel therapeutic targets for treating both BBB dysfunction and pain.

Public Health Relevance

Pain afflicts more than 85 million people in the United States each year, causing tremendous suffering and costing billions of dollars in medical treatments and lost productivity. Pain-induced blood-brain barrier (BBB) dysfunction significantly alters delivery into the brain of clinically important drugs used to treat pain. This NIH grant proposal will study key mechanisms of BBB changes induced by pain and inflammation, and will be critical in aiding the discovery of new therapeutic drugs for treating BBB dysfunction and pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042652-10
Application #
8243605
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2001-12-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$572,694
Indirect Cost
$192,471
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Thompson, Brandon J et al. (2014) P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac. PLoS One 9:e88516
Davis, Thomas P; Sanchez-Covarubias, Lucy; Tome, Margaret E (2014) P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery. Adv Pharmacol 71:25-44
Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Thompson, Brandon J et al. (2014) Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? Curr Pharm Des 20:1422-49
Ronaldson, Patrick T; Finch, Jessica D; Demarco, Kristin M et al. (2011) Inflammatory pain signals an increase in functional expression of organic anion transporting polypeptide 1a4 at the blood-brain barrier. J Pharmacol Exp Ther 336:827-39
Ronaldson, Patrick T; Demarco, Kristin M; Sanchez-Covarrubias, Lucy et al. (2009) Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain. J Cereb Blood Flow Metab 29:1084-98
Campos, Christopher R; Ocheltree, Scott M; Hom, Sharon et al. (2008) Nociceptive inhibition prevents inflammatory pain induced changes in the blood-brain barrier. Brain Res 1221:6-13
McCaffrey, Gwen; Seelbach, Melissa J; Staatz, William D et al. (2008) Occludin oligomeric assembly at tight junctions of the blood-brain barrier is disrupted by peripheral inflammatory hyperalgesia. J Neurochem 106:2395-409
Willis, C L; Davis, T P (2008) Chronic inflammatory pain and the neurovascular unit: a central role for glia in maintaining BBB integrity? Curr Pharm Des 14:1625-43
Brooks, Tracy A; Nametz, Nicole; Charles, Rachael et al. (2008) Diclofenac attenuates the regional effect of lambda-carrageenan on blood-brain barrier function and cytoarchitecture. J Pharmacol Exp Ther 325:665-73
Seelbach, Melissa J; Brooks, Tracy A; Egleton, Richard D et al. (2007) Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein. J Neurochem 102:1677-90

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