Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Pain Medicine & Neuroscience >> Drug Interactions at the Human Blood-Brain Barrier
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Research Focus Areas:
Pain Medicine & Neuroscience

Drug Interactions at the Human Blood-Brain Barrier

Principal Investigators

J. D. Unadkat, Ph.D., K. B. Domino, M.D., M.P.H., A. Collier, M.D., et al.

Description

The blood brain barrier (BBB) is a significant barrier to delivery of drugs to the central nervous system (CNS) and in removal of potential toxins produced within the CNS (e.g. beta-amyloid). In contrast to the endothelial cell barrier in other organs, the BBB has tight junctions that prevent significant paracellular diffusion. Although lipophilic drugs are capable of readily diffusing across the BBB, several efflux transporters present at this barrier can significantly reduce the entry of these drugs into the CNS. Prominent amongst these is P-glycoprotein (P-gp), an ABC transporter encoded by the multi-drug resistance 1 (MDR1) gene. Due to its high expression at the BBB and its wide substrate selectivity, P-gp is widely believed to be the most important transporter in modulating the entry of drugs into the CNS.

The functional importance of P-gp at the BBB was confirmed with the development of the mdr1a(-/-) mice. With ablation of P-gp at the BBB, administration of P-gp substrate drugs to mdr1a(-/-) mice results in a dramatic increase in the brain distribution of these drugs. For example, compared to the wild type mouse, the brain:blood concentration ratio of the anti-cancer taxanes, paclitaxel and docetaxel, is increased 6 to 28-fold. Based on the above data and those in the rat, it has been widely presumed that P-gp at the human BBB plays an important role in limiting CNS drug distribution. If true, this could have several consequences. First, P-gp could limit effective therapy of CNS disorders such as primary and metastatic brain tumors, HIV-associated dementia and epilepsy. For example, despite excellent in vitro efficacy of anticancer drugs, brain tumors are notoriously difficult to treat. This is because the BBB (including P-gp) impedes drug delivery to the tumor. In order to improve drug therapy of brain tumors, a potential strategy is to chemically inhibit P-gp and therefore circumvent the P-gp BBB. Another consequence of high P-gp activity at the human BBB is that inadvertent inhibitory P-gp drug interactions are likely to be profound. Such interactions could result in a significant increase in central nervous system (CNS) efficacy or toxicity of drugs that are P-gp substrates. Indeed, data in the literature support this conclusion. Quinidine, a P-gp inhibitor, increases the neurotoxicity of loperamide, an opioid and a P-gp substrate.

Therefore, our specific aims are designed to address the following key question: (i) Can P-gp activity at the human BBB be inhibited with currently approved FDA drugs? To answer this question, we will utilize the development by our laboratory of a novel, innovative and non-invasive, Positron Emission Tomography (PET) imaging method, which enables the measurement of P-gp based drug interactions at the human BBB.

Pain Medicine & Neuroscience:
Research Projects

An Internet CBT Intervention for Pediatric Chronic Pain and Disability
T. Palermo, Ph.D.
Cervical Sympathetic Block in Patients with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemmorhage
M. DePinto, M.D., M.M. Treggiari, M.D., Ph.D., M.P.H.
Controlling Pain After Trauma
D. Patterson, Ph.D., S. R. Sharar, M.D., M. Jensen, Ph.D., H. Hoffman, Ph.D., et al.
Cytokine and Neurotransmitter Interactions in Sleep Regulation
M. R. Opp, Ph.D., L. Imeri, M.D.
Disability from Pediatric Traumatic Brain Injury
P Rivara, M.D., M. S. Vavilala, M.D.
Drug Interactions at the Human Blood-Brain Barrier
J. D. Unadkat, Ph.D., K. B. Domino, M.D., M.P.H., A. Collier, M.D., et al.
Effectiveness of Oxymorphone for Acute Postoperative Pain Pediatric Subjects
S.Bhananker, M.D.
Identifying Virtual Reality Analgesia Mechanisms by Pharmacologic Manipulation
S. R. Sharar, M. D., D.A. Patterson, Ph.D, H.Hunter, Ph.D., et al.
Influence of Dexmedetomidine on the Evoked Potentials During Spine Surgery
Rozet, M.D.
Innovations In Pediatric Pain Research
T. Palermo, Ph.D.
Ketorolac in Surgical Infants: Pharmacokinetics/Analgesia
A.M. Lynn, M.D.
Mechanism Of Action Of Volatile Anesthetics
P.G. Morgan, M.D.
Memantine for Post-Operative Pain Control in the Opiate-Tolerant Patient
G. Terman, M.D., Ph.D.
Modulation of Pruritus by Spinal Cannabinoids
G. W. Terman, M.D.,Ph.D.
Molecular Mechanisms of Sleep Responses to Viral Infection
James Krueger, PhD (WSU: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats
Gayle Page, DNSc, RN (Johns Hopkins: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neurologic Injury after Non-Supine Surgery Registry
L. A. Lee, M.D., L. Stephens, Ph.D., K. B. Domino, M.D., M.P.H., K. L. Posner, Ph.D.
Neuron-glial communication and brain aging
Paula Bickford, PhD (University of South Florida: PI); Carmelina Gemma, PhD (co-investigator/subcontract PI)
Neuronal-Glial Dialogue and Cognition
Carmelina Gemma, PhD (PI)
Neurotoxic Effects of Volatile Anesthetics in C. Elegans
P.G. Morgan, M.D.
Open Label Study of the Safety and Efficacy of Conivaptan (Vaprisol) to raise serum sodium levels in patients with severe traumatic brain injury
M. M. Treggiari, M.D., Ph.D., M.P.H., S. A. Deem, M.D., N.D. Yanez III, Ph.D.
Optimizing the Control of Pain from Severe Burns
D. Patterson, Ph.D.; S R. Sharar, MD; D. Heimbach, MD., J Doctor, Ph.D.
Patient Perceptions of the Benefits of Long-Term Opioid Therapy (PLOT) Initiative-Beliefs and Behaviors
D. C. Turk, Ph.D., J. P. Robinson., M.D., R. Landau, M.D.
Sepsis Outcomes and Aging: Role of Sleep Disruption and the Blood Brain Barrier
Mark R. Opp, PhD (PI); William A. Banks, MD (co-investigator); Richard M. Raymond, PhD (co-investigator)
Shared Decision Making in Orthopaedic Spine Surgery to Improve Patient Safety
K. B. Domino,M.D, M.P.H.; K. L. Posner, Ph.D. et al.
Sleep-Wake Disturbances in Adolescents with Chronic Pain Research
T. Palermo, Ph.D.
Subgroups of FMS: Symptoms, Beliefs & Tailored Treatments
D.C. Turk, Ph.D., J. Robinson, M.D., Ph.D.
Subjective and Neuroimaging Assessment of Combined Opioid and Virtual Reality Analgesia
S. R. Sharar, M.D., T. Richards, Ph.D.
Ultrasound Guided Rectus Sheath Block for Post-Operative Pain Control Following Umbilical Hernia Repair
S. Flack, M.D.
University of Washington Urologic Chronic Pelvic Pain Syndromes Discovery Center
D. S. Buchwald, M.D., N. Jimenez, M. D., et al.
Web-based CBT for Opioid-treated Chronic Pain Patients With Aberrant Behavior
Rosenblum, Ph.D., D.C. Turk, Ph.D.