Pain and the blood–brain barrier: obstacles to drug delivery

Trojano, 1992, Blood–brain barrier changes in multiple sclerosis, Ital. J. Neurol. Sci., 13, 55 Kalaria, 1996, Cerebral vessels in ageing and Alzheimer’s disease, Pharmacol. Ther., 72, 193, 10.1016/S0163-7258(96)00116-7 Dallasta, 1999, Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis, Am. J. Pathol., 155, 1915, 10.1016/S0002-9440(10)65511-3 Kim, 1997, Blood–brain barrier permeability during the development of experimental bacterial meningitis in the rat, Exp. Neurol., 145, 253, 10.1006/exnr.1997.6458 Huber, 2001, Inflammatory pain alters blood–brain barrier permeability and tight junctional protein expression, Am. J. Physiol. Heart Circ. Physiol., 280, H1241, 10.1152/ajpheart.2001.280.3.H1241 Huber, 2002, Blood–brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain, Am. J. Physiol. Heart Circ. Physiol., 283, H1531, 10.1152/ajpheart.00027.2002 Reese, 1967, Fine structural localization of a blood–brain barrier to exogenous peroxidase, J. Cell Biol., 34, 207, 10.1083/jcb.34.1.207 Drewes, 2001, Molecular architecture of the brain microvasculature: perspective on blood–brain transport, J. Mol. Neurosci., 16, 93, 10.1385/JMN:16:2-3:93 Huber, 2001, Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier, Trends Neurosci., 24, 719, 10.1016/S0166-2236(00)02004-X Butt, 1990, Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study, J. Physiol., 429, 47, 10.1113/jphysiol.1990.sp018243 Furuse, 1999, Manner of interaction of heterogeneous claudin species within and between tight junction strands, J. Cell Biol., 147, 891, 10.1083/jcb.147.4.891 Hirase, 1997, Occludin as a possible determinant of tight junction permeability in endothelial cells, J. Cell Sci., 110, 1603, 10.1242/jcs.110.14.1603 Martin-Padura, 1998, Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration, J. Cell Biol., 142, 117, 10.1083/jcb.142.1.117 Haskins, 1998, ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin, J. Cell Biol., 141, 199, 10.1083/jcb.141.1.199 Itoh, 1999, Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH terminii of claudins, J. Cell Biol., 147, 1351, 10.1083/jcb.147.6.1351 Hirokawa, 1982, Interactions between actin filaments and between actin filaments and membranes in quick-frozen and deeply etched hair cells of the chick ear, J. Cell Biol., 95, 249, 10.1083/jcb.95.1.249 Bentzel, 1976, Effect of plant cytokinins on microfilaments and tight junction permeability, Nature, 264, 666, 10.1038/264666a0 Stevenson, 1994, Concentration-dependent effects of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells, J. Cell Sci., 107, 367, 10.1242/jcs.107.3.367 Tsukamoto, 1997, Tight junction proteins form large complexes and associate with the cytoskeleton in an ATP depletion model for reversible junction assembly, J. Biol. Chem., 272, 16133, 10.1074/jbc.272.26.16133 Nusrat, 2000, Tight junctions are membrane microdomains, J. Cell Sci., 113, 1771, 10.1242/jcs.113.10.1771 Schlegel, 2001, The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction, Cytokine Growth Factor Rev., 12, 41, 10.1016/S1359-6101(00)00022-8 Madara, 1992, The movement of solutes and cells across tight junctions, Ann. N. Y. Acad. Sci., 664, 47, 10.1111/j.1749-6632.1992.tb39748.x Stuart, 1995, Regulated assembly of tight junctions by protein kinase C, Proc. Natl. Acad. Sci. USA, 92, 6072, 10.1073/pnas.92.13.6072 Willott, 1993, The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions, Proc. Natl. Acad. Sci. USA, 90, 7834, 10.1073/pnas.90.16.7834 Izumi, 1998, An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3, J. Cell Biol., 143, 95, 10.1083/jcb.143.1.95 Gumbiner, 1996, Cell adhesion: the molecular basis of tissue architecture and morphogenesis, Cell, 84, 345, 10.1016/S0092-8674(00)81279-9 Nigam, 1992, Changes in intracellular calcium during the development of epithelial polarity and junctions, Proc. Natl. Acad. Sci. USA, 89, 6162, 10.1073/pnas.89.13.6162 Stuart, 1994, Critical role for intracellular calcium in tight junction biogenesis, J. Cell. Physiol., 159, 423, 10.1002/jcp.1041590306 Stuart, 1996, Dependence of epithelial intercellular junction biogenesis on thapsigargin-sensitive intracellular calcium stores, J. Biol. Chem., 271, 13636, 10.1074/jbc.271.23.13636 Abbott, 1996, Transporting therapeutics across the blood–brain barrier, Mol. Med. Today, 2, 106, 10.1016/1357-4310(96)88720-X Egleton, 1997, Bioavailability and transport of peptides and peptide drugs into the brain, Peptides, 18, 1431, 10.1016/S0196-9781(97)00242-8 Taylor, 2002, The impact of efflux transporters in the brain on the development of drugs for CNS disorders, Clin. Pharmakokinet., 41, 81, 10.2165/00003088-200241020-00001 Diamond, 1969, Molecular forces governing non-electrolyte permeation through cell membranes, Proc. Royal Soc., 172, 273, 10.1098/rspb.1969.0022 Pardridge, 1979, Transport of steroid hormones through the rat blood–brain barrier. Primary role of albumin bound hormone, J. Clin. Invest., 64, 145, 10.1172/JCI109433 Weber, 1991, Distribution and analgesia of [3H][d-Pen2,d-Pen5]enkephalin and two halogenated analogs after intravenous administration, J. Pharm. Exp. Ther., 259, 1109 Weber, 1993, Assessment of an in vitro blood–brain barrier model using several [Met5] enkephalin opioid analogs, J. Pharm. Exp. Ther., 266, 1649 Tsuji, 1999, Carrier-mediated or specialized transport of drugs across the blood–brain barrier, Adv. Drug Deliv. Rev., 36, 277, 10.1016/S0169-409X(98)00084-2 Tamai, 2000, Transporter-mediated permeation of drugs across the blood–brain barrier, J. Pharm. Sci., 89, 1371, 10.1002/1520-6017(200011)89:11<1371::AID-JPS1>3.0.CO;2-D Brightman, 1969, Junctions between intimately apposed cell membranes in the vertebrate brain, J. Cell Biol., 40, 648, 10.1083/jcb.40.3.648 Fishman, 1987, Receptor-mediated transcytosis of transferrin across the blood–brain barrier, J. Neurosci. Res., 18, 299, 10.1002/jnr.490180206 Descamps, 1996, Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells, Am. J. Physiol., 270, H1149 King, 1985, Receptor-mediated transport of insulin across endothelial cells, Science (Washington, DC), 227, 1583, 10.1126/science.3883490 Dehouck, 1994, Upregulation of the low density lipoprotein receptor at the blood–brain barrier: intercommunications between brain capillary endothelial cells and astrocytes, J. Cell Biol., 126, 465, 10.1083/jcb.126.2.465 Kumagi, 1987, Adsorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain microvessel, J. Biol. Chem., 262, 15214, 10.1016/S0021-9258(18)48160-4 Tamai, 1997, Structure-internalization relationship for adsorptive-mediated endocytosis of basic peptides at the blood–brain barrier, J. Pharm. Exp. Ther., 280, 410 Guillot, 1990, Fluid-phase endocytosis by primary cultures of bovine brain microvessel endothelial cell monolayers, Microvasc. Res., 39, 1, 10.1016/0026-2862(90)90055-V Stanimirovic, 1996, Angiotensin II-induced fluid phase endocytosis in human cerebromicrovascular endothelial cells is regulated by the inositol-phosphate signaling pathway, J. Cell. Physiol., 169, 455, 10.1002/(SICI)1097-4652(199612)169:3<455::AID-JCP6>3.0.CO;2-N Bart, 2000, The blood–brain barrier and oncology: new insights into function and modulation, Cancer Treat. Rev., 26, 449, 10.1053/ctrv.2000.0194 Potschka, 2002, P-Glycoprotein-mediated efflux of penobarbital, lamotrigine, and felbamate at the blood–brain barrier: evidence from microdialysis experiments in rats, Neurosci. Lett., 327, 173, 10.1016/S0304-3940(02)00423-8 Banks, 1999, Physiology and pathology of the blood–brain barrier: implication for microbial pathogenesis, drug delivery and neurodegenerative disorders, J. Neurovirol., 5, 538, 10.3109/13550289909021284 Hedaya, 1989, Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit, J. Pharm. Sci., 78, 716, 10.1002/jps.2600780903 Wang, 1995, Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion, J. Pharm. Sci., 84, 871, 10.1002/jps.2600840717 Schinkel, 1995, Absence of the mdr1a p-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporine, J. Clin. Invest., 96, 1698, 10.1172/JCI118214 Suzuki, 1989, Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system, J. Pharmacol. Exp. Ther., 250, 979 Ooie, 1997, Kinetic evidence for active efflux transport across the blood–brain barrier of quinolone antibiotics, J. Pharmacol. Exp. Ther., 283, 293 Adkison, 1994, Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroids plexus to the efficient efflux of valproic acid from the central nervous system, J. Pharmacol. Exp. Ther., 268, 797 Schinkel, 1994, Disruption of the mouse mdr1a p-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs, Cell, 77, 491, 10.1016/0092-8674(94)90212-7 De Graaf, 1996, P-glycoprotein confers methotrexate resistance in 3T6 cells with deficient carrier-mediated methotrexate uptake, Proc. Natl. Acad. Sci. USA, 93, 11238, 10.1073/pnas.93.3.1238 Dickenson, 1999, The roles of spinal receptors in nociceptive responses, 23 Rivest, 2001, How circulating cytokines trigger the neural circuits that control the hypothalamic–pituitary–adrenal axis, Psychoneuroendocrinology, 26, 761, 10.1016/S0306-4530(01)00064-6 Ferreira, 1988, Interleukin-1β as a potent hyperalgesic agent antagonized by a tripeptide analogue, Nature, 334, 698, 10.1038/334698a0 Cunha, 1991, Interleukin-8 as a mediator of sympathetic pain, Br. J. Pharmacol., 104, 765, 10.1111/j.1476-5381.1991.tb12502.x Perkins, 1994, Bradykinin B1 and B2 receptor mechanisms and cytokine-induced hyperalgesia in the rat, Can. J. Physiol. Pharmacol., 73, 832, 10.1139/y95-113 Watkins, 1994, Characterization of cytokine-induced hyperalgesia, Brain Res., 654, 15, 10.1016/0006-8993(94)91566-0 Watkins, 1995, Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia, Brain Res., 692, 244, 10.1016/0006-8993(95)00715-3 Perkins, 1999, Interactions between kinins and the inflammatory pain process, 103 Fernandes, 2002, The role of cytokines in osteoarthritis pathophysiology, Biorheology, 39, 237 Banks, 1991, Human interleukin (IL) 1 alpha, murine IL-1 alpha and murine IL-1 beta are transported from blood to brain in the mouse by a shared saturable mechanism, J. Pharmacol. Exp. Ther., 259, 988 Gutierrez, 1993, Murine tumor necrosis factor alpha is transported from blood to brain in the mouse, J. Neuroimmunol., 47, 169, 10.1016/0165-5728(93)90027-V Hopkins, 1995, Cytokines and the nervous system I: expression and recognition, Trends Neurosci., 18, 83, 10.1016/0166-2236(95)93881-W LeMay, 1990, Role of interleukin 6 in fever in rats, Am. J. Physiol., 258, R798 Cooper, 1991, Mechanisms of early and late hypermetabolism and fever after localized tissue injury, Am. J. Physiol., 261, E698 Breder, 1988, Interleukin-1 immunoreactive innervation of the human hypothalamus, Science, 240, 321, 10.1126/science.3258444 Gatti, 1993, Induction of tumor necrosis factor alpha mRNA in the brain after peripheral endotoxin treatment comparison with interleukin-1 family and interleukin-6, Brain Res., 624, 291, 10.1016/0006-8993(93)90090-A Romero, 1993, Bacterial lipopolysaccharide induction of IL-6 in rat telencephalic cells is mediated in part by IL-1, Neuroendocrinology, 57, 892, 10.1159/000126450 Schobitz, 1993, Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain, Eur. J. Neurosci., 5, 1426, 10.1111/j.1460-9568.1993.tb00210.x Godessart, 2001, Chemokines in autoimmune disease, Curr. Opin. Immunol., 13, 670, 10.1016/S0952-7915(01)00277-1 Rossi, 2000, The biology of chemokines and their receptors, Annu. Rev. Immunol., 18, 217, 10.1146/annurev.immunol.18.1.217 Locati, 2002, Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes, J. Immunol., 168, 3557, 10.4049/jimmunol.168.7.3557 Aliberti, 2000, CCR5 provides a signal for microbial-induced production of IL-12 by CD8α+ dendritic cells, Nat. Immunol., 1, 83, 10.1038/76957 Braun, 2000, Selective suppression of IL-12 production by chemoattractants, J. Immunol., 164, 3009, 10.4049/jimmunol.164.6.3009 Bajetto, 2002, Characterization of chemokines and their receptors in the central nervous system: physiopathological implications, J. Neurochem., 82, 1311, 10.1046/j.1471-4159.2002.01091.x Springer, 1995, Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration, Annu. Rev. Physiol., 57, 827, 10.1146/annurev.ph.57.030195.004143 Cid, 2000, Cell adhesion molecules in the development of inflammatory infiltrates in giant cell arteritis, Arthritis Rheum., 43, 184, 10.1002/1529-0131(200001)43:1<184::AID-ANR23>3.0.CO;2-N Albelda, 1994, Adhesion molecules and inflammatory injury, FASEB J., 8, 504, 10.1096/fasebj.8.8.8181668 Wang, 1995, Induced expression of adhesion molecules following focal brain ischemia, J. Neurotrauma, 12, 825, 10.1089/neu.1995.12.825 Howard, 1998, NF-κB is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells, Neurosci. Lett., 248, 199, 10.1016/S0304-3940(98)00239-0 Harlan, 2002, Leukocyte–endothelial interactions: clinical trials of anti-adhesion therapy, Crit. Care Med., 30, S214, 10.1097/00003246-200205001-00007 Huang, 1993, Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells, J. Cell Biol., 120, 1371, 10.1083/jcb.120.6.1371 Milner, 2002, Developmental regulation of β1 integrins during angiogenesis in the central nervous system, Mol. Cell. Neurosci., 20, 616, 10.1006/mcne.2002.1151 Jones, 1996, Integrins: possible functions in the adult CNS, Trends Neurosci., 19, 68, 10.1016/0166-2236(96)89623-8 Pinkstaff, 1999, Integrin subunit gene expression is regionally differentiated in adult brain, J. Neurosci., 19, 1541, 10.1523/JNEUROSCI.19-05-01541.1999 Springer, 1990, Adhesion receptors of the immune system, Nature, 346, 425, 10.1038/346425a0 Sobel, 1998, Endothelial cell integrin laminin receptor expression in multiple sclerosis lesions, Am. J. Pathol., 153, 405, 10.1016/S0002-9440(10)65584-8 Merrill, 1997, Inflammatory events at the blood–brain barrier: regulation of adhesion molecules, cytokines, and chemokines by reactive nitrogen and oxygen species, Brain, Behav. Immun., 11, 245, 10.1006/brbi.1997.0496 Galis, 2002, Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly, Circ. Res., 90, 251, 10.1161/res.90.3.251 Birkedal-Hansen, 1993, Role of cytokines and inflammatory mediators in tissue destruction, J. Periodontal Res., 28, 500, 10.1111/j.1600-0765.1993.tb02113.x Paul, 1998, Matrix metalloproteinases contribute to the blood–brain barrier disruption during bacterial meningitis, Ann. Neurol., 44, 592, 10.1002/ana.410440404 Mun-Bryce, 1998, Gelatinase B modulates selective opening of the blood–brain barrier during inflammation, Am. J. Physiol., 274, R1203 Mun-Bryce, 1998, Matrix metalloproteinases in cerebrovascular disease, J. Cereb. Blood Flow Metab., 18, 1163, 10.1097/00004647-199811000-00001 Galis, 1994, Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion, Circ. Res., 75, 181, 10.1161/01.RES.75.1.181 Libby, 1995, Cytokines regulate genes involved in atherosclerosis, 158 McEarchern, 1991, Expression cloning of a rat B2 bradykinin receptor, Proc. Natl. Acad. Sci. USA, 88, 7724, 10.1073/pnas.88.17.7724 Hall, 1992, Bradykinin receptors: pharmacological properties and biological roles, Pharmacol. Ther., 56, 131, 10.1016/0163-7258(92)90016-S Hess, 1992, Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor, Biochem. Biophys. Res. Commun., 184, 260, 10.1016/0006-291X(92)91187-U Armstrong, 1970, Pain, vol. 25, 434 Coleman, 1970, Kallikrein–kinin system in pathologic conditions, vol. 25, 569 Regoli, 1980, Pharmacology of bradykinin and related kinins, Am. Soc. Pharmacol. Exp. Ther., 32, 1 Oh-Ishi, 1987, Roles of kallikrein–kinin system in acute inflammation: studies on high- and low-molecular weight kininogens-deficient rats (B/N-Katholiek strain), Agents Actions, 21, 384, 10.1007/BF01966523 Burgess, 1989, Second messengers involved in the action of bradykinin on cultured sensory neurons, J. Neurosci., 9, 3314, 10.1523/JNEUROSCI.09-09-03314.1989 Rueff, 1993, Sensitization of peripheral afferent fibres in the in vitro neonatal rat spinal cord-tail by bradykinin and prostaglandins, Neuroscience, 54, 527, 10.1016/0306-4522(93)90272-H Walker, 1995, Kinins and kinin receptor systems in the nervous system, Neurochem. Int., 26, 1, 10.1016/0197-0186(94)00114-A Lewis, 1985, (125I) Tyr-bradykinin binding in primary rat brain cultures, Brain Res., 346, 263, 10.1016/0006-8993(85)90859-5 Snider, 1984, Bradykinin receptor mediated cyclic GMP formation in a nerve cell population (murine neuroblastoma, clone NIE-115), J. Neurochem., 43, 1749, 10.1111/j.1471-4159.1984.tb06104.x Campbell, 1993, Bradykinin peptides in kidney, blood and other tissues of the rat, Hypertension, 21, 155, 10.1161/01.HYP.21.2.155 Hosli, 1993, Autoradiographic localization of binding sites for neuropeptide Y and bradykinin on astrocytes, Neuroreport, 4, 159, 10.1097/00001756-199302000-00011 Wahl, 1999, Effects of bradykinin in the cerebral circulation, Acta Physiol. Hung., 86, 155 Parpura, 1994, Glutamate-mediated astrocyte-neuron signaling, Nature, 369, 744, 10.1038/369744a0 Phipps, 1991, A new view of prostaglandin-E regulation of the immune response, Immunol. Today, 12, 349, 10.1016/0167-5699(91)90064-Z Goetzl, 1995, Specificity of expression and effects of eicosanoid mediators in normal physiology and human diseases, FASEB J., 9, 1051, 10.1096/fasebj.9.11.7649404 Moncada, 1985, Prostaglandins, prostacyclin and thromboxane A2, 660 Harris, 2002, Prostaglandins as modulators of immunity, Trends Immunol., 23, 144, 10.1016/S1471-4906(01)02154-8 Hinz, 2000, Prostaglandin E(2) upregulates cyclooxygenase-2 expression in lipopolysaccharide-stimulated RAW 264.7 macrophages, Biochem. Biophys. Res. Commun., 272, 744, 10.1006/bbrc.2000.2859 Ikegami, 2001, The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by lipopolysaccharide in C3H/HeN peritoneal macrophages, J. Immunol., 166, 4689, 10.4049/jimmunol.166.7.4689 Katsuura, 1989, Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides, Endocrinology, 124, 3125, 10.1210/endo-124-6-3125 Rettori, 1992, Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus, Proc. Natl. Acad. Sci. USA, 89, 11543, 10.1073/pnas.89.23.11543 Nogawa, 1997, Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage, J. Neurosci., 17, 2746, 10.1523/JNEUROSCI.17-08-02746.1997 Mark, 2001, Tumor necrosis factor-α induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells, J. Pharmacol. Exp. Ther., 297, 1051 Vegeto, 2001, Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia, J. Neurosci., 21, 1809, 10.1523/JNEUROSCI.21-06-01809.2001 Yamagata, 2001, Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever, J. Neurosci., 21, 2669, 10.1523/JNEUROSCI.21-08-02669.2001 Yamagata, 1993, Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids, Neuron, 11, 371, 10.1016/0896-6273(93)90192-T Adams, 1996, Cyclooxygenase-2 induction in cerebral cortex: an intracellular response to synaptic excitation, J. Neurochem., 66, 6, 10.1046/j.1471-4159.1996.66010006.x Marcheselli, 1996, Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus, J. Biol. Chem., 271, 24794, 10.1074/jbc.271.40.24794 Repovic, 2002, Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia, J. Neurosci., 22, 5334, 10.1523/JNEUROSCI.22-13-05334.2002 Van Wagoner, 2000, Oncostatin M regulation of interleukin-6 expression in astrocytes: biphasic regulation involving the mitogen-activated protein kinases ERK1/2 and p38, J. Neurochem., 75, 563, 10.1046/j.1471-4159.2000.0750563.x Ruprecht, 2001, Effects of oncostatin M on human cerebral endothelial cells and expression in inflammatory brain lesions, J. Neuropathol. Exp. Neurol., 60, 1087, 10.1093/jnen/60.11.1087 Murase, 1989, Tachykinins modulate multiple ionic conductances in voltage-clamped rat spinal dorsal horn neurons, J. Neruophys., 61, 854, 10.1152/jn.1989.61.4.854 Harris, 1998, Using c-fos as a neural marker of pain, Brain Res. Bull., 45, 1, 10.1016/S0361-9230(97)00277-3 Pernow, 1983, Substance P, Pharmacol. Rev., 5, 85 Wiesenfeld-Hallin, 1984, Immunoreactive calcitonin gene-regulated peptide and substance P coexist in sensory neurons of the spinal cord and interact in spinal behavioral responses of the rat, Neurosci. Lett., 52, 199, 10.1016/0304-3940(84)90374-4 Dickenson, 1994, NMDA receptor antagonists as analgesics, 173 Dickenson, 1995, Spinal cord pharmacology of pain, Br. J. Anaesth., 75, 193, 10.1093/bja/75.2.193 1997 Collingridge, 1990, Excitatory amino acid receptors and synaptic plasticity, Trends Pharm. Sci., 11, 290, 10.1016/0165-6147(90)90011-V Matute, 1994, Glutamate receptors in astrocytic end-feet, Neuroreport, 5, 1205, 10.1097/00001756-199406020-00011 Krizbai, 1998, Expression of glutamate receptors on cultured cerebral endothelial cells, J. Neurosci. Res., 54, 814, 10.1002/(SICI)1097-4547(19981215)54:6<814::AID-JNR9>3.0.CO;2-3 Morley, 1998, Evidence that functional glutamate receptors are not expressed on rat or human cerebromicrovascular endothelial cells, J. Cereb. Blood Flow Metab., 18, 396, 10.1097/00004647-199804000-00008 Collard, 2002, Neutrophil-derived glutamate regulates vascular endothelial barrier function, J. Biol. Chem., 277, 14801, 10.1074/jbc.M110557200 St’astny, 2002, Main subunits of ionotropic glutamate receptors are expressed in rat brain microvessel, Neurol. Res., 24, 93, 10.1179/016164102101199468 Miller, 2002, Neuroendocrine aspects of the response to stress, Metabolism, 51, 5, 10.1053/meta.2002.33184 Turnbull, 1999, Regulation of the hypothalamic–pituitary–adrenal axis by cytokines: actions and mechanisms of action, Physiol. Rev., 79, 1, 10.1152/physrev.1999.79.1.1 Elenkov, 2002, Stress hormones, proinflammatory and inflammatory cytokines, and autoimmunity, Ann. N. Y. Acad. Sci., 966, 290, 10.1111/j.1749-6632.2002.tb04229.x Webster, 2002, Neuroendocrine regulation of immunity, Annu. Rev. Immunol., 20, 125, 10.1146/annurev.immunol.20.082401.104914 Haselton, 1989, Chromatographic demonstration of reversible changes in endothelial permeability, J. Appl. Physiol., 67, 2032, 10.1152/jappl.1989.67.5.2032 Dejana, 1997, Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis, J. Clin. Invest., 100, S7 Nieuw Amerongen, 2000, Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases, Circ. Res., 87, 335, 10.1161/01.RES.87.4.335 Baldwin, 2001, Mechanics of endothelial cell architechture and vascular permeability, Crit. Rev. Biomed. Eng., 29, 247, 10.1615/CritRevBiomedEng.v29.i2.20 de Vries, 1996, The influence of cytokines on the integrity of the blood–brain barrier in vitro, J. Neuroimmunol., 64, 37, 10.1016/0165-5728(95)00148-4 Gloor, 1997, Interleukin-1 modulates protein tyrosine phosphatase activity and permeability of brain endothelial cells, Biochem. Biophys. Res. Commun., 239, 804, 10.1006/bbrc.1997.7557 Citi, 1992, Protein kinase inhibitors prevent junction dissociation induced by low extracelllular calcium in MDCK epithelial cells, J. Cell Biol., 117, 169, 10.1083/jcb.117.1.169 Volberg, 1992, The effect of tyrosine-specific protein phosphorylation on the assembly of adherens-type junctions, EMBO J., 11, 1733, 10.1002/j.1460-2075.1992.tb05225.x Staddon, 1995, Evidence that tyrosine phosphorylation may increase tight junction permeability, J. Cell Sci., 108, 609, 10.1242/jcs.108.2.609 Bolton, 1998, Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo, Neuroscience, 86, 1245, 10.1016/S0306-4522(98)00058-X Blamire, 2000, Interleukin-1 beta-induced changes in blood–brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study, J. Neurosci., 20, 8153, 10.1523/JNEUROSCI.20-21-08153.2000 Wachtel, 2001, Down-regulation of occludin expression in astrocytes by tumour necrosis factor (TNF) is mediated via TNF type-1 receptor and nuclear factor-kappa B activation, J. Neurochem., 78, 155, 10.1046/j.1471-4159.2001.00399.x Descamps, 1997, Effects of tumor necrosis factor on receptor-mediated endocytosis and barrier functions of blood–brain capillary endothelial cell monolayers, J. Neuroimmunol., 74, 173, 10.1016/S0165-5728(96)00226-3 Edens, 2000, Modulation of epithelial and endothelial paracellular permeability by leukocytes, Adv. Drug Deliv. Rev., 41, 315, 10.1016/S0169-409X(00)00049-1 Boven, 2000, Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia, Neuropathol. Appl. Neurobiol., 26, 356, 10.1046/j.1365-2990.2000.00255.x Partridge, 1993, A 96-kDa gelatinase induced by TNF-alpha contributes to increased microvascular endothelial permeability, Am. J. Physiol., 265, L438 Wachtel, 1999, Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition, J. Cell Sci., 112, 4347, 10.1242/jcs.112.23.4347 Alexander, 2002, Extracellular matrix, junctional integrity, and matrix metalloproteinase interactions in endothelial permeability regulation, J. Anat., 200, 561, 10.1046/j.1469-7580.2002.00057.x Sarker, 2000, Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat, J. Physiol., 528, 177, 10.1111/j.1469-7793.2000.00177.x Sanovich, 1995, Pathway across blood–brain barrier opened by the bradykinin agonist, RMP-7, Brain Res., 705, 125, 10.1016/0006-8993(95)01143-9 Prat, 2000, Kinin B1 receptor expression and function on human brain endothelial cells, J. Neuropathol. Exp. Neurol., 59, 896, 10.1093/jnen/59.10.896 Cioni, 1998, Enhanced secretion of substance P by cytokine-stimulated rat brain endothelium cultures, J. Neuroimmunol., 84, 76, 10.1016/S0165-5728(97)00235-X Catalan, 1989, Substance P stimulates translocation of protein kinase C in brain microvessels, Biochem. Biophys. Res. Commun., 164, 595, 10.1016/0006-291X(89)91501-5 Moreno, 2002, Characterization of calcitonin gene-regulated peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture, Neuropharmacology, 42, 270, 10.1016/S0028-3908(01)00176-9 Baethmann, 1988, Mediators of brain edema and secondary brain damage, Crit. Care Med., 16, 972, 10.1097/00003246-198810000-00008 Westergren, 1994, Concentrations of amino acids in extracellular fluid after opening of the blood–brain barrier by intracarotid infusion of protamine sulfate, J. Neurochem., 62, 159, 10.1046/j.1471-4159.1994.62010159.x Mayhan, 1996, Glutamate-induced disruption of the blood–brain barrier in rats, Stroke, 27, 965, 10.1161/01.STR.27.5.965 Bolton, 1997, MK-801 limits neurovascular dysfunction during experimental allergic encephalomyelitis, J. Pharm. Exp. Ther., 282, 397 Mori, 1998, Effects of mild and moderate hypothermia on cerebral metabolism and glutamate in an experimental head injury, Acta Neurochir. Suppl. (Wien), 71, 222 Kustova, 1999, Increased blood–brain barrier permeability in LP-BM5-infected mice is mediated by neuroexcitatory mechanisms, Brain Res., 839, 153, 10.1016/S0006-8993(99)01734-5 Nishida, 1996, Increases in brain platelet activating factor were inhibited by the N-methyl-d-aspartate antagonist MK-801 in mice infected with the LP-BM5 murine leukemia virus, J. Neurochem., 66, 433, 10.1046/j.1471-4159.1996.66010433.x Bolton, 1998, Differential blood–brain barrier breakdown and leukocyte recruitment following excitotoxic lesions in juvenile and adult rats, Exp. Neurol., 154, 231, 10.1006/exnr.1998.6927 Rosch, 1979, Stress and illness, J. Am. Med. Assoc., 242, 427, 10.1001/jama.242.5.417 Mei-Tal, 1970, The role of psychological process in a somatic disorder: multiple sclerosis. 1. The emotional setting of illness onset and exacerbation, Psychosom. Med., 32, 67, 10.1097/00006842-197001000-00006 Warren, 1982, Emotional stress and the development of multiple sclerosis: case control evidence of a relationship, J. Chronic Dis., 35, 821, 10.1016/0021-9681(82)90047-9 Goodin, 1999, The relationship of MS to physical trauma and psychological stress, Neurology, 52, 1737, 10.1212/WNL.52.9.1737 Galli, 1993, New concepts about the mast cell, New Engl. J. Med., 328, 257, 10.1056/NEJM199301283280408 Theoharides, 1990, Mast cells: the immune gate to the brain, Life Sci., 46, 607, 10.1016/0024-3205(90)90129-F Karalis, 1991, Autocrine or paracrine inflammatory actions of corticotrophin-releasing hormone in vivo, Science, 254, 421, 10.1126/science.1925600 Theoharides, 1998, Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects, Endocrinology, 139, 403, 10.1210/en.139.1.403 Esposito, 2001, Acute stress increases permeability of the blood–brain barrier through activation of brain mast cells, Brain Res., 888, 117, 10.1016/S0006-8993(00)03026-2 de Vries, 1996, Effect of endotoxin on permeability of bovine cerebral endothelial cell layers in vitro, J. Pharmacol. Exp. Ther., 277, 1418 Gregg, 1992, Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues and morphologic evidence of toxicity, J. Clin. Oncol., 10, 795, 10.1200/JCO.1992.10.5.795 Minami, 1998, Penetration of cisplatin into mouse brain by lipopolysaccharide, Toxicology, 130, 107, 10.1016/S0300-483X(98)00103-6 Higa, 1995, Severe, disabling neurologic toxicity following cisplatin retreatment, Ann. Pharmacother., 29, 134, 10.1177/106002809502900206 Anda, 1997, Effect of tumor necrosis factor-alpha on the permeability of bovine brain microvessel endothelial cell monolayers, Neurol. Res., 19, 369, 10.1080/01616412.1997.11758599 Wu, 1999, Neuroprotection with noninvasive neurotrophin delivery to the brain, Proc. Natl. Acad. Sci. USA, 96, 254, 10.1073/pnas.96.1.254 Song, 2002, Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood–brain barrier delivery vector, J. Pharmacol. Exp. Ther., 301, 605, 10.1124/jpet.301.2.605 Wu, 2002, Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood–brain barrier drug delivery system, J. Drug Target., 10, 239, 10.1080/10611860290022679 Boado, 1998, Drug delivery of antisense molecules to the brain for treatment of Alzheimer’s disease and cerebral AIDS, J. Pharm. Sci., 87, 1308, 10.1021/js9800836 Li, 2000, Brain delivery of biotinylated NGF bounded to an avidin–transferrin conjugate, J. Nat. Toxins, 9, 73 Swaiman, 1991, Hallervorden–Spatz syndrome and brain iron metabolism, Arch. Neurol., 48, 1285, 10.1001/archneur.1991.00530240091029 Jenner, 1994, Oxidative damage in neurodegenerative disease, Lancet, 344, 796, 10.1016/S0140-6736(94)92347-7 Aisen, 1999, Iron metabolism, Curr. Opin. Chem. Biol., 3, 200, 10.1016/S1367-5931(99)80033-7 Qian, 1998, Expression of iron transport proteins and excessive iron accumulation in the brain in neurodegenerative disorders, Brain Res. Rev., 27, 257, 10.1016/S0165-0173(98)00012-5 Qian, 2001, Brain iron transport and neurodegeneration, Trends Mol. Med., 7, 103, 10.1016/S1471-4914(00)01910-9 Dykstra, 1993, Microdialysis study of zidovudine (AZT) transport in rat brain, J. Pharmacol. Exp. Ther., 267, 1227 Wong, 1993, Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis, J. Pharmacol. Exp. Ther., 264, 899 Wang, 1997, Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid, J. Pharm. Sci., 86, 1484, 10.1021/js950330v Deguchi, 2000, Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood–brain barrier, Life Sci., 66, 649, 10.1016/S0024-3205(99)00637-2 Dombrowski, 2001, Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy, Epilepsia, 42, 1501, 10.1046/j.1528-1157.2001.12301.x Felix, 2002, P-glycoprotein expression in rat brain endothelial cells: evidence for regulation by transient oxidative stress, J. Neurochem., 80, 64, 10.1046/j.0022-3042.2001.00660.x Piquette-Miller, 1998, Decreased expression and activity of P-glycoprotein in rat liver during acute inflammation, Pharm. Res., 15, 706, 10.1023/A:1011962818051 Sukhai, 2001, Decreased expression of P-glycoprotein in interleukin-1 beta and interleukin-6 treated rat hepatocytes, Inflamm. Res., 50, 362, 10.1007/PL00000257 Hartmann, 2002, Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia, J. Pharmacol. Exp. Ther., 303, 273, 10.1124/jpet.102.039404 Sakaeda, 2000, Enhancement of transport of d-melphalan analogue by conjugation with l-glutamate across bovine brain microvessel endothelial cell monolayers, J. Drug Target., 8, 195, 10.3109/10611860008996865 Sakaeda, 2001, Conjugation with l-glutamate for in vivo brain drug delivery, J. Drug Target., 9, 23, 10.3109/10611860108995630 Emerich, 2001, The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood–brain barrier: from concept to clinical evaluation, Clin. Pharmacokinet., 40, 105, 10.2165/00003088-200140020-00003 Dean, 1999, Cereport (RMP-7) increases carboplatin levels in brain tumors after pretreatment with dexamethasone, Neuro-oncology, 1, 268, 10.1093/neuonc/1.4.268 Bartus, 2000, Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival, J. Pharmacol. Exp. Ther., 293, 903 Emerich, 2000, Intravenous cereport (RMP-7) enhances delivery of hydrophilic chemotherapeutics and increases survival in rats with metastatic tumors in the brain, Pharm. Res., 17, 1212, 10.1023/A:1026462629438