Medical Neurobiology Commons^™

Nf1 Loss And Ras Hyperactivation In Oligodendrocytes Induce Nos-Driven Defects In Myelin And Vasculature, Debra A. Mayes, Tilat A. Rizvi, Haley E. Titus-Mitchell, Rachel Oberst, Georgianne M. Ciraolo, Charles V. Vorhees, Andrew P. Robinson, Stephen D. Miller, Jose A. Cancelas, Anat O. Stemmer-Rachamimov, Nancy Ratner

Neuroscience, Cell Biology & Physiology Faculty Publications

Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1-NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor …

Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan

Neuroscience Faculty Patents

A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.

Alternations Of Nmda And Gabab Receptor Function In Development: A Potential Animal Model Of Schizophrenia, Monica Bolton

UNLV Theses, Dissertations, Professional Papers, and Capstones

Schizophrenia is a debilitating mental disorder that affects up to 3% of the world population. The behavioral symptoms are categorized into positive and negative symptoms, which appear during late adolescence/early adulthood. Unfortunately, the underlying cellular and molecular mechanisms of the disease are poorly understood. Several hypotheses exist to explain mechanisms contributing to these behavioral alterations. One model proposes that a reduced function of the NMDA glutamate receptor on specific GABAergic interneurons may be responsible for deficits in schizophrenia. Post-mortem investigations provide evidence of reductions in both glutamate and GABA-related proteins in patients with schizophrenia. Further, GABAergic interneurons that are activated …

Exploring Volatile General Anesthetic Binding To A Closed Membrane-Bound Bacterial Voltage-Gated Sodium Channel Via Computation., S G Raju, Annika F Barber, David N Lebard, Michael L Klein, Vincenzo Carnevale

Department of Neuroscience Faculty Papers

Despite the clinical ubiquity of anesthesia, the molecular basis of anesthetic action is poorly understood. Amongst the many molecular targets proposed to contribute to anesthetic effects, the voltage gated sodium channels (VGSCs) should also be considered relevant, as they have been shown to be sensitive to all general anesthetics tested thus far. However, binding sites for VGSCs have not been identified. Moreover, the mechanism of inhibition is still largely unknown. The recently reported atomic structures of several members of the bacterial VGSC family offer the opportunity to shed light on the mechanism of action of anesthetics on these important ion …

Cannabis And Psychosis: Transition To Psychosis, Amresh Srivastava, Kristen , Terpstra, Yves Bureau

Data and Test Instruments

Cannabis has been implicated as a risk factor for the development of schizophrenia, however, but the pathway of cannabis causing psychosis is not well understood. It appears that cannabis does not cause any structural changes per say but deficits in areas of the brain responsible for memory and emotion do show some changes. Recent studies suggest that cannabinoids such as CB1 have a pharmacological profile similar to that of atypical antipsychotic drugs. This mechanisms may involve dopamine, GABA, and glutamate neurotransmission; It is still not known if these changes are transitory or permanent, and whether or not they contribute to …

The Effect Of Nerve Growth Factor (Ngf) Incorporation Into Swine Intestinal Submucosa (Sis) Suture Material On The Healing Process In Gastrocnemius Muscle, Nicole K. Alexander

PCOM Biomedical Studies Student Scholarship

The repair of gastrocnemius muscle incisions were evaluated histologically in a rat model. Comparisons were made between carbon dioxide laser and scalpel incisions closed with sutures prepared from Swine Intestinal Submucosa (SIS) with and without added Nerve Growth Factor. This study was conducted in conjunction with two other studies, one comparing epidermal repair and the other comparing kinesthetic changes post-operatively in the same animal model. Thirty-five days post-surgery the animals were euthanized and an area of muscular tissue encompassing the operative site was excised and evaluated microscopically for the following: presence of macrophages, integrity of the muscle, leukocytes present within …

The Effects Of Chronic Calcium Dysregulation On Behavioral And Pathological Features Of Alzheimer's Disease, Jonathan Sabbagh

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is unknown. Recent studies have implicated alterations in calcium homeostasis as a pathogenic contributor to AD. Calcium dysregulation has been observed in aged and AD brains, an event which could potentially facilitate the development of multiple pathologies observed in AD. Specifically, disrupting intracellular calcium levels in vitro has been demonstrated to increase amyloid-beta (Aβ) production, tau phosphorylation, and neuronal loss. However, there is a paucity of data on the behavioral and biochemical consequences of chronic in vivo perturbation of calcium homeostasis. In a series of experiments designed to evaluate the …

Celiac Disease And Neurological Symptoms, Lauren V. Cook

Senior Honors Theses

New research has revealed that Celiac disease, an autoimmune illness affecting the small intestine, has more ties with neurological side effects than once was thought. The classic and most well known presentation of Celiac disease is gastrointestinal, including symptoms such as abdominal pains, nausea, diarrhea, and flatulence. Researchers have more recently found a correlation between Celiac disease and neurological illnesses such as epilepsy, depression, dementia, and ADHD. Physician awareness of the disease and the neurological side of the illness should be heightened in order for patients to receive earlier diagnosis and a better quality of life. Because of the difficulty …

Microglial Disruption In Young Mice With Early Chronic Exposure To Lead, Christina Sobin, Mayra Flores Montoya, Natali Parisi, Tanner Schaub, Miguel Cervantes, Rodrigo Armijos

Selected Works Temporary Series

The mechanisms by which early chronic lead (Pb) exposure alters brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams’ drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) …

The P38Α Mapk Regulates Microglial Responsiveness To Diffuse Traumatic Brain Injury, Adam D. Bachstetter, Rachel K. Rowe, Machi Kaneko, Danielle Goulding, Jonathan Lifshitz, Linda J Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Neuropathology after traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, using in vitro models, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. From these findings, we hypothesized that the p38α signaling pathway in microglia could be contributing to the secondary neuropathologic sequelae after …

Deficiency In P38Β Mapk Fails To Inhibit Cytokine Production Or Protect Neurons Against Inflammatory Insult In In Vitro And In Vivo Mouse Models, Bin Xing, Adam D. Bachstetter, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

The p38 MAPK pathway plays a key role in regulating the production of proinflammatory cytokines, such as TNFα and IL-1β, in peripheral inflammatory disorders. There are four major isoforms of p38 MAPK (p38α, β, δ, γ), with p38α and p38β the targets of most p38 MAPK inhibitor drugs. Our previous studies demonstrated that the p38α MAPK isoform is an important contributor to stressor-induced proinflammatory cytokine up-regulation and neurotoxicity in the brain. However, the potential role of the p38β MAPK isoform in CNS proinflammatory cytokine overproduction and neurotoxicity is poorly understood. In the current studies, we used primary microglia from wild …

Impairment Of Trkb-Psd-95 Signaling In Angelman Syndrome, Cong Cao, Mengia S. Rioult-Pedotti, Paolo Migani, Crystal J. Yu, Rakesh Tiwari, Keykavous Parang, Mark R. Spaller

Dartmouth Scholarship

Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) …

Associations Between Cadmium Exposure And Neurocognitive Test Scores In A Cross-Sectional Study Of Us Adults, Timothy Ciesielski, David C. Bellinger, Joel Schwartz, Russ Hauser, Robert O. Wright

Dartmouth Scholarship

Background: Low-level environmental cadmium exposure and neurotoxicity has not been well studied in adults. Our goal was to evaluate associations between neurocognitive exam scores and a biomarker of cumulative cadmium exposure among adults in the Third National Health and Nutrition Examination Survey (NHANES III).

Methods: NHANES III is a nationally representative cross-sectional survey of the U.S. population conducted between 1988 and 1994. We analyzed data from a subset of participants, age 20–59, who participated in a computer-based neurocognitive evaluation. There were four outcome measures: the Simple Reaction Time Test (SRTT: visual motor speed), the Symbol Digit Substitution Test (SDST: attention/perception), …

Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan

Neuroscience Faculty Patents

A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.

Nanotubes As Mitochondrial Uncouplers, Patrick G. Sullivan

Neuroscience Faculty Patents

A method of uncoupling mitochondria in a subject including administering nanotubes to the subject in a therapeutically effective amount, wherein the nanotubes are self-rectifying is provided. A method of decreasing reactive oxygen species and decreasing detrimental loading of Ca²⁺ into mitochondria is provided, including administering a pharmaceutically effective amount of nanotubes into the subject. A method of reducing weight, treating cancer, reducing the effects of traumatic brain injury, or reducing the effects of ageing, in a subject including administering a pharmaceutically effective amount of nanotubes into the subject is also provided.

Impairment Of Trkb-Psd-95 Signaling In Angelman Syndrome, Cong Cao, Mengia S. Rioult-Pedotti, Paolo Migani, Crystal J. Yu, Rakesh Tiwari, Keykavous Parang, Mark R. Spaller, Dennis J. Goebel, John Marshall

Pharmacy Faculty Articles and Research

Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) …

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Decreased Neuroinflammation And Increased Brain Energy Homeostasis Following Environmental Enrichment After Mild Traumatic Brain Injury Is Associated With Improvement In Cognitive Function, Teresita L. Briones, Julie Woods, Magdalena Rogozinska

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Persistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI). Because of the lack of success of most TBI interventions and the documented benefits of environmental enrichment (EE) in enhancing brain plasticity, here we focused our study on use of EE in regulating injury-induced neuroinflammation and disruptions in energy metabolism in the prefrontal cortex and hippocampus. Adult male Wistar rats were used in the study and randomly assigned to receive either: mild TBI (mTBI) using the controlled cortical injury model or sham surgery. Following surgery, rats from each group were further randomized …

Effects Of Intranasally Administered Dnsp-11 On The Central Dopamine System Of Normal And Parkinsonian Fischer 344 Rats, James H. Sonne

Theses and Dissertations--Neuroscience

Due to the blood-brain barrier, delivery of many drugs to the brain has required intracranial surgery which is prone to complication. Here we show that Dopamine Neuron Stimulating Peptide 11 (DNSP-11), following non-invasive intranasal administration, protects dopaminergic neurons from a lesion model of Parkinson’s disease in the rat. A significant and dose-dependent increase in an index of dopamine turnover (the ratio of DOPAC to dopamine) was observed in the striatum of normal young adult Fischer 344 rats by whole-tissue neurochemistry compared to vehicle administered controls.

Among animals challenged with a moderate, unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the substantia nigra, those …

Glutamate Dysregulation And Hippocampal Dysfunction In Epileptogenesis, Seth R. Batten

Theses and Dissertations--Medical Sciences

Epileptogenesis is the complex process of the brain developing epileptic acitivity. Due to the role of glutamate and the hippocampus in synaptic plasticity a dysregulation in glutamate neurotransmission and hippocampal dysfunction are implicated in the process of epileptogenesis. However, the exact causal factors that promote epileptogenesis are unknown.

We study presynaptic proteins that regulate glutamate neurotransmission and their role in epileptogenesis. The presynaptic protein, tomosyn, is believed to be a negative regulator of glutamate neurotransmission; however, no one has studied the effects of this protein on glutamate transmission in vivo. Furthermore, evidence suggests that mice lacking tomosyn have a …

Retinal Vascular Biomarkers For Early Detection And Monitoring Of Alzheimer's Disease, Shawn Frost, Yogi Kanagasingam, Hamid Sohrabi, J Vignarajan, P Bourgeat, Olivier Salvado, Victor Villemagne, Christopher Rowe, S Lance Macaulay, Cassandra Szoeke, Kathryn A. Ellis, David Ames, Colin L. Masters, Stephanie Rainey-Smith, Ralph N. Martins

Research outputs 2013

The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes …

Human Calmodulin Methyltransferase: Expression, Activity On Calmodulin, And Hsp90 Dependence, Sophia Magen, Roberta Magnani, Sitvanit Haziza, Eli Hershkovitz, Robert Houtz, Franca Cambi, Ruti Parvari

Horticulture Faculty Publications

Deletion of the first exon of calmodulin-lysine N-methyltransferase (CaM KMT, previously C2orf34) has been reported in two multigene deletion syndromes, but additional studies on the gene have not been reported. Here we show that in the cells from 2p21 deletion patients the loss of CaM KMT expression results in accumulation of hypomethylated calmodulin compared to normal controls, suggesting that CaM KMT is essential for calmodulin methylation and there are no compensatory mechanisms for CaM methylation in humans. We have further studied the expression of this gene at the transcript and protein levels. We have identified 2 additional …

Metabotropic Glutamate Receptor 5 In The Medial Prefrontal Cortex: Role In Cocaine Sensitization And Addiction, Kristin Marie Timmer

Theses and Dissertations (ETD)

Cocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drugseeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 …

Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge

Pharmacy Faculty Articles and Research

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …

Targeting Astrocytes Ameliorates Neurologic Changes In A Mouse Model Of Alzheimer's Disease, Jennifer L. Furman, Diana M. Sama, John C. Gant, Tina L. Beckett, M. Paul Murphy, Adam D. Bachstetter, Linda J. Van Eldik, Christopher M. Norris

Pharmacology and Nutritional Sciences Faculty Publications

Astrocytes are the most abundant cell type in the brain and play a critical role in maintaining healthy nervous tissue. In Alzheimer's disease (AD) and most other neurodegenerative disorders, many astrocytes convert to a chronically "activated" phenotype characterized by morphologic and biochemical changes that appear to compromise protective properties and/or promote harmful neuroinflammatory processes. Activated astrocytes emerge early in the course of AD and become increasingly prominent as clinical and pathological symptoms progress, but few studies have tested the potential of astrocyte-targeted therapeutics in an intact animal model of AD. Here, we used adeno-associated virus (AAV) vectors containing the astrocyte-specific …

Antioxidant Rescue Of Nf1/Ras-Induced Myelin And Vasculature Dysfunction, Debra A. Mayes, Tilat A. Rizvi, Shyra J. Miller, Rachel Oberst, Anat Stemmer-Rachamimov, Nancy Ratner

Neuroscience, Cell Biology & Physiology Faculty Publications

No abstract provided.

Malignant Peripheral Nerve Sheath Tumor (Mpnst): An Overview With Emphasis On Pathology, Imaging And Management Strategies, Timothy C. Beer

Department of Neurosurgery Faculty Papers

Presentation: 20 slides

MPNSTs are rare malignancies that are classically associated with pre-existing plexiform neurofibromas in neurofibromatosis type 1 (NF-1) patients, but also occur in association with radiation as well as sporadically in patients with no known risk factors. The typical presentation of sporadic MPNST is a new painless enlarging mass. The typical presentation of MPNST in an NF-1 patient is rapid enlargement or new onset of pain associated with a pre-existing plexiform neurofibroma. Although both MPNST and benign neurofibromas share in common the absence of neurofibromin function due to loss of both NF-1 alleles, malignant transformation to MPNST requires …

Inhibition Of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations And Ca2+ Dysregulation In Aged Rats, Diana M. Sama, Hafiz Mohmmad Abdul, Jennifer L. Furman, Irina A. Artiushin, David E. Szymkowski, Stephen W. Scheff, Christopher M. Norris

Graduate Center for Gerontology Faculty Publications

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits …

Management Of Sexual Disorders In Spinal Cord Injured Patients., Vafa Rahimi-Movaghar, Alexander R Vaccaro

Department of Neurosurgery Faculty Papers

Spinal cord injured (SCI) patients have sexual disorders including erectile dysfunction (ED), impotence, priapism, ejaculatory dysfunction and infertility. Treatments for erectile dysfunction include four steps. Step 1 involves smoking cessation, weight loss, and increasing physical activity. Step 2 is phosphodiesterase type 5 inhibitors (PDE5I) such as Sildenafil (Viagra), intracavernous injections of Papaverine or prostaglandins, and vacuum constriction devices. Step 3 is a penile prosthesis, and Step 4 is sacral neuromodulation (SNM). Priapism can be resolved spontaneously if there is no ischemia found on blood gas measurement or by Phenylephrine. For anejaculatory dysfunction, massage, vibrator, electrical stimulation and direct surgical biopsy …

Mitogen Activated Protein Kinase Phosphatase-1 Prevents The Development Of Tactile Sensitivity In A Rodent Model Of Neuropathic Pain, Christian Ndong, Russell P. Landry, Joyce A. Deleo, Edgar A. Romero-Sandoval

Dartmouth Scholarship

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of …