Pain is a dominant symptom associated with acute and chronic inflammation. Pain-induced blood-brain barrier (BBB) dysfunction alters CNS delivery of analgesic drugs including opioids. A clear comprehension of biological mechanisms involved in drug transport across the BBB is essential to clarify CNS uptake of opioids and their efficacy in pain treatment. Furthermore, investigation of pathophysiological features of peripheral inflammatory pain (PIP) (i.e., changes in serum concentrations of cytokines such as IL-6 and TGF-2s) will enable an improved understanding of the regulation of drug transporters (i.e., P-glycoprotein (P-gp), Multidrug Resistance Proteins (Mrps), Breast Cancer Resistance Protein (BCRP;also known as ABCG2), organic anion transporting polypeptides (Oatps)) and/or tight junction proteins (i.e., claudin-3 and -5, occludin, ZO-1) at the BBB and how these processes relate to CNS opioid delivery. Additionally, pain management regimens may involve multiple drugs, which can lead to harmful drug-drug interactions. These drug-drug interactions may involve changes in BBB transport mechanisms associated with functional expression of nuclear receptors [i.e., pregnane-X-receptor (PXR), constitutive androstane receptor (CAR)]. The activation of PXR and/or CAR may lead to altered efficacy and/or CNS toxicity of opioids. The ability of nuclear receptors to regulate drug transport may differ between acute and chronic pain. These differences may be related to expression changes in PXR/CAR, which may be associated with variations in serum/cerebrospinal fluid cytokine levels. Our hypothesis is that changes in transport of commonly prescribed opioid analgesics and novel therapeutic opioid peptides will occur due to alterations in the functional expression of putative membrane drug transporters and tight junction proteins. We propose that these changes in transport are caused by cytokine signaling and/or activity of nuclear receptors during PIP.
The aims of this grant will be investigated using a combination of in vivo methods as well as biochemical and molecular techniques established and working in our laboratory. This proposal will elucidate mechanisms that can alter CNS opioid delivery and will point to novel strategies to improve PIP treatment.

Public Health Relevance

PIP may lead to BBB dysfunction, including changes in opioid permeability. This grant application is clinically relevant since PIP-associated changes in BBB xenobiotic permeability can be a factor in altered efficacy and CNS toxicity sometimes observed following opioid administration. This study may point to novel ways to improve CNS opioid delivery and to avoid unwanted opioid side effects during the treatment of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011271-14
Application #
8307459
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (03))
Program Officer
Purohit, Vishnudutt
Project Start
1997-08-05
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$486,088
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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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
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Slosky, Lauren M; Thompson, Brandon J; Sanchez-Covarrubias, Lucy et al. (2013) Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 84:774-86
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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
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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

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