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.
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.
|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|
|Abdullahi, Wazir; Brzica, Hrvoje; Ibbotson, Kathryn et al. (2017) Bone morphogenetic protein-9 increases the functional expression of organic anion transporting polypeptide 1a4 at the blood-brain barrier via the activin receptor-like kinase-1 receptor. J Cereb Blood Flow Metab 37:2340-2345|
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|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|
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|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|
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