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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Arizona
Schools of Medicine
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Yang, Junzhi; Reilly, Bianca G; Davis, Thomas P et al. (2018) Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity. Pharmaceutics 10:
Sandweiss, Alexander J; Cottier, Karissa E; McIntosh, Mary I et al. (2017) 17-?-Estradiol induces spreading depression and pain behavior in alert female rats. Oncotarget 8:114109-114122
Lochhead, Jeffrey J; Ronaldson, Patrick T; Davis, Thomas P (2017) Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System. AAPS J 19:910-920
Schaefer, Charles P; Tome, Margaret E; Davis, Thomas P (2017) The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse. Fluids Barriers CNS 14:32
Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T (2017) Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery? AAPS J 19:931-939
Bosetti, Francesca; Galis, Zorina S; Bynoe, Margaret S et al. (2016) ""Small Blood Vessels: Big Health Problems?"": Scientific Recommendations of the National Institutes of Health Workshop. J Am Heart Assoc 5:
Tome, Margaret E; Herndon, Joseph M; Schaefer, Charles P et al. (2016) P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain. J Cereb Blood Flow Metab 36:1913-1928
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
Ronaldson, Patrick T; Davis, Thomas P (2015) Targeting transporters: promoting blood-brain barrier repair in response to oxidative stress injury. Brain Res 1623:39-52

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