Pain afflicts over 116 million Americans annually and costs an estimated $635 billion dollars in medical treatments and lost productivity. The treatment of pain (both acute/post-surgical and chronic) often involves opioid analgesics. We have shown that peripheral inflammatory pain (PIP) promotes BBB dysfunction characterized by changes in expression and localization of efflux transporter and tight junction (TJ) proteins as well as increased paracellular permeability (i.e., leak). The clinical relevance of these changes i altered brain uptake of opioid analgesics. In this renewal, we propose to test the novel hypothesis that BBB dysfunction during PIP, which alters paracellular permeability and CNS delivery of opioid analgesics, can be modulated by therapeutic targeting of pathology-induced changes in trafficking of P- glycoprotein (Pgp) and of TJ proteins occludin and claudins that are critical to the formation and integrity of TJ oligomeric protein assemblies.
Two specific aims will test this hypothesis.
Aim 1 : To determine how PIP-induced changes in Pgp trafficking result in increased Pgp drug efflux activity. In this aim, we will identify components of Pgp storage compartment(s) isolated from cerebral microvessels (Aim 1A). We will also correlate changes in Pgp opioid efflux activity with changes in Pgp trafficking over a 1-72 hr time course (one-hit or rechallenge) (Aim 1B). Since production of reactive oxygen species (ROS) is a critical component of pain/inflammation, we will evaluate the effect of administration of TEMPOL (i.e., 4-hydroxy-2,2,6,6-tetramethylpiperidine-N- oxyl), a ROS scavenger, on Pgp trafficking as well as brain uptake and analgesic efficacy of opioids over a 1-72 hr time course of PIP (one-hit or rechallenge) (Aim 1C).
Aim 2 : To examine how PIP-induced changes in TJ protein trafficking modulate paracellular BBB permeability. In this aim, we will identify proteins associated with TJs isolated from cerebral microvessels (Aim 2A). We will also correlate changes in paracellular BBB permeability with changes in protein-protein interactions that cause changes in intracellular trafficking of occludin and claudins over a 1-72 hr time course of PIP (one-hit or rechallenge) (Aim 2B). We will then evaluate the effect of TEMPOL administration on occludin/claudin trafficking, on BBB paracellular permeability to codeine and codeine efficacy over a 1-72 hr time course of PIP (one-hit or rechallenge).
(Aim 2 C). Our goal in this renewal is to discover novel therapeutic targets for treating both pain and pain-induced BBB dysfunction by defining the role of protein trafficking in promoting changes in BBB structure/function that lead to altered CNS drug delivery during PIP.

Public Health Relevance

We have previously shown that pain alters two critical components of the BBB, tight junctions that limit the ability of a drug to cross into the brain fro the blood and drug efflux pumps that actively prevent drugs from accumulating in the brain. The effects of these BBB changes on opioid drug therapy are dramatic alterations in effectiveness of these drugs to relieve pain and/or significant CNS side effects. This grant proposal will expand on these findings and directly impact public health in the United States by determining and developing novel methods to control BBB changes during pain and enable provision of optimal pain relief with opioid analgesic drugs.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS042652-12
Application #
8606777
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Tome, Margaret E; Schaefer, Charles P; Jacobs, Leigh M et al. (2015) Identification of P-glycoprotein co-fractionating proteins and specific binding partners in rat brain microvessels. J Neurochem 134:200-10
Davis, Thomas P; Abbruscato, Thomas J; Egleton, Richard D (2015) Peptides at the blood brain barrier: Knowing me knowing you. Peptides 72:50-6
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
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
Ronaldson, Patrick T; Davis, Thomas P (2013) Gabapentin and diclofenac reduce opioid consumption in patients undergoing tonsillectomy: a result of altered CNS drug delivery? Arch Trauma Res 2:97-8
Ronaldson, Patrick T; Davis, Thomas P (2013) Targeted drug delivery to treat pain and cerebral hypoxia. Pharmacol Rev 65:291-314
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
Ronaldson, Patrick T; Davis, Thomas P (2012) Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des 18:3624-44
McCaffrey, Gwen; Staatz, William D; Sanchez-Covarrubias, Lucy et al. (2012) P-glycoprotein trafficking at the blood-brain barrier altered by peripheral inflammatory hyperalgesia. J Neurochem 122:962-75

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