Physiology Commons^™

Analgesic Tolerance Of Opioid Agonists In Mutant Mu-Opioid Receptors Expressed In Sensory Neurons Following Intrathecal Plasmid Gene Delivery, Guangwen Li, Fei Ma, Yanping Gu, Li-Yen Mae Huang

Physiology Faculty Publications

Background: Phosphorylation sites in the C-terminus of mu-opioid receptors (MORs) are known to play critical roles in the receptor functions. Our understanding of their participation in opioid analgesia is mostly based on studies of opioid effects on mutant receptors expressed in in vitro preparations, including cell lines, isolated neurons and brain slices. The behavioral consequences of the mutation have not been fully explored due to the complexity in studies of mutant receptors in vivo. To facilitate the determination of the contribution of phosphorylation sites in MOR to opioid-induced analgesic behaviors, we expressed mutant and wild-type human MORs (hMORs) in sensory …

Molecular Events In The Cell Types Of The Olfactory Epithelium During Adult Neurogenesis, Paula M. Heron, Arnold J. Stromberg, Patrick Breheny, Timothy S. Mcclintock

Physiology Faculty Publications

BACKGROUND: Adult neurogenesis, fundamental for cellular homeostasis in the mammalian olfactory epithelium, requires major shifts in gene expression to produce mature olfactory sensory neurons (OSNs) from multipotent progenitor cells. To understand these dynamic events requires identifying not only the genes involved but also the cell types that express each gene. Only then can the interrelationships of the encoded proteins reveal the sequences of molecular events that control the plasticity of the adult olfactory epithelium.

RESULTS: Of 4,057 differentially abundant mRNAs at 5 days after lesion-induced OSN replacement in adult mice, 2,334 were decreased mRNAs expressed by mature OSNs. Of the …

Tricellulin Deficiency Affects Tight Junction Architecture And Cochlear Hair Cells, Gowri Nayak, Sue I. Lee, Rizwan Yousaf, Stephanie E. Edelmann, Claire Trincot, Christina M. Van Itallie, Ghanshyam P. Sinha, Maria Rafeeq, Sherri M. Jones, Inna A. Belyantseva, James M. Anderson, Andrew Forge, Gregory I. Frolenkov, Saima Riazuddin

Physiology Faculty Publications

The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while …

Mouse Strain Determines Cardiac Growth Potential, Carmen Kiper, Barry Grimes, Gary Van Zant, Jonathan Satin

Physiology Faculty Publications

RATIONALE: The extent of heart disease varies from person to person, suggesting that genetic background is important in pathology. Genetic background is also important when selecting appropriate mouse models to study heart disease. This study examines heart growth as a function of strain, specifically C57BL/6 and DBA/2 mouse strains.

OBJECTIVE: In this study, we test the hypothesis that two strains of mice, C57BL/6 and DBA/2, will produce varying degrees of heart growth in both physiological and pathological settings.

METHODS AND RESULTS: Differences in heart dimensions are detectable by echocardiography at 8 weeks of age. Percentages of cardiac progenitor cells (c-kit+ …

Dexamethasone Rapidly Increases Gaba Release In The Dorsal Motor Nucleus Of The Vagus Via Retrograde Messenger-Mediated Enhancement Of Trpv1 Activity, Andrei V. Derbenev, Bret N. Smith

Physiology Faculty Publications

Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX) modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV). Whole-cell patch-clamp recordings revealed that DEX (1-10 µM) rapidly (i.e. within three minutes) increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs) in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were …

Down's Syndrome, Neroinflammation, And Alzheimer Neuropathogenesis, Donna M. Wilcock, W. Sue T. Griffin

Physiology Faculty Publications

Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. In addition to the mental deficiencies and physical anomalies noted at birth, triplication of chromosome 21 gene products results in the neuropathological and cognitive changes of Alzheimer's disease (AD). Mapping of the gene that encodes the precursor protein (APP) of the β-amyloid (Aβ) present in the Aβ plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. The discovery of …

Voluntary Exercise Protects Against Methamphetamine-Induced Oxidative Stress In Brain Microvasculature And Disruption Of The Blood--Brain Barrier, Michal Toborek, Melissa J. Seelbach, Cetewayo S. Rashid, Ibolya E. András, Lei Chen, Minseon Park, Karyn A. Esser

Physiology Faculty Publications

BACKGROUND: There is no effective therapeutic intervention developed targeting cerebrovascular toxicity of drugs of abuse, including methamphetamine (METH). We hypothesize that exercise protects against METH-induced disruption of the blood--brain barrier (BBB) by enhancing the antioxidant capacity of cerebral microvessels and modulating caveolae-associated signaling. Mice were subjected to voluntary wheel running for 5 weeks resembling the voluntary pattern of human exercise, followed by injection with METH (10 mg/kg). The frequency, duration, and intensity of each running session were monitored for each mouse via a direct data link to a computer and the running data are analyzed by Clock labTM Analysis software. …

Neural Circuit Mechanisms Of Post-Traumatic Epilepsy, Robert F. Hunt, Jeffery A. Boychuk, Bret N. Smith

Physiology Faculty Publications

Traumatic brain injury (TBI) greatly increases the risk for a number of mental health problems and is one of the most common causes of medically intractable epilepsy in humans. Several models of TBI have been developed to investigate the relationship between trauma, seizures, and epilepsy-related changes in neural circuit function. These studies have shown that the brain initiates immediate neuronal and glial responses following an injury, usually leading to significant cell loss in areas of the injured brain. Over time, long-term changes in the organization of neural circuits, particularly in neocortex and hippocampus, lead to an imbalance between excitatory and …

Molecular Remodeling Of Tip Links Underlies Mechanosensory Regeneration In Auditory Hair Cells, Artur A. Indzhykulian, Ruben Stepanyan, Anastasiia Nelina, Kateri J. Spinelli, Zubair M. Ahmed, Inna A. Belyantseva, Thomas B. Friedman, Peter G. Barr-Gillespie, Gregory I. Frolenkov

Physiology Faculty Publications

Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously …

Does Naloxone Reinstate Secondary Hyperalgesia In Humans After Resolution Of A Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study, Manuel P. Pereira, Mads U. Werner, Thomas K. Ringsted, Michael C. Rowbotham, Bradley K. Taylor, Joergen B. Dahl

Physiology Faculty Publications

INTRODUCTION: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.

METHODS: Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury …

Summary Of Papers Presented At The 2012 Seventh International Cough Symposium, Peter V. Dicpinigaitis, Giovanni A. Fontana, Lu-Yuan Lee, Milos Tatar

Physiology Faculty Publications

Twenty six papers were presented as posters in the Seventh International Symposium on Cough; 12 papers were presented in the Basic Science of Cough session, and 14 papers presented in the Clinical Science of Cough session. These papers explored a wide spectrum of cough-related areas including pathophysiological mechanisms, treatment and detection of cough, and symptom assessment and perception, and were grouped into several general themes for facilitate the discussion. Studies presented in these posters have provided new information that should improve our knowledge on the basic physiology and pharmacology of cough, and the peripheral and central neural mechanisms involved in …

Derivation Of Multivariate Syndromic Outcome Metrics For Consistent Testing Across Multiple Models Of Cervical Spinal Cord Injury In Rats, Adam R. Ferguson, Karen-Amanda Irvine, John C. Gensel, Jessica L. Nielson, Amity Lin, Johnathan Ly, Mark R. Segal, Rajiv R. Ratan, Jacqueline C. Bresnahan, Michael S. Beattie

Physiology Faculty Publications

Spinal cord injury (SCI) and other neurological disorders involve complex biological and functional changes. Well-characterized preclinical models provide a powerful tool for understanding mechanisms of disease; however managing information produced by experimental models represents a significant challenge for translating findings across research projects and presents a substantial hurdle for translation of novel therapies to humans. In the present work we demonstrate a novel 'syndromic' information-processing approach for capitalizing on heterogeneous data from diverse preclinical models of SCI to discover translational outcomes for therapeutic testing. We first built a large, detailed repository of preclinical outcome data from 10 years of basic …

Excitatory Amino Acids Display Compartmental Disparity Between Plasma And Synovial Fluid In Clinical Arthropathies, Terry A. Mcnearney, Karin N. Westlund

Physiology Faculty Publications

BACKGROUND: Previous studies have demonstrated elevated levels of excitatory amino acids (EAA) glutamate (Glu) and aspartate (Asp) in the synovial fluid (SF) of patients with active arthritis. The source of SF EAA concentrations are thought in large part to be secondary to passive diffusion from the plasma across synovial membranes and less so, reflective of local synovial pathology.

OBJECTIVE: This descriptive report assesses the hypothesis that the SF EAA levels reflect inflammatory processes of the joint and are not dependent on plasma levels.

METHODS: Simultaneously drawn plasma and SF samples were obtained from 14 recently deceased cadavers and 10 patients …

The Feasibility Of A Fiber Optic Laser Approach To Relieving Lymphedematous Syndrome: A Case Report, Beniamino Palmieri, Alessandro Di Cerbo, Valentina Rottigni, Gregorio Fistetto, Tommaso Iannitti

Physiology Faculty Publications

Here we report a case of successful fiber optic laser treatment of lymphedema in a swollen arm post mastectomy. At the moment, this procedure has only anecdotal evidence to justify its use, but in our experience is a feasible, minimally invasive day-stay procedure which has been demonstrated to be safe and effective. Further nonhomogeneous case pooling and follow-up would enable guidelines and definite surgical protocols for its use to be implemented.

Rapid Glucocorticoid-Induced Activation Of Trp And Cb1 Receptors Causes Biphasic Modulation Of Glutamate Release In Gastric-Related Hypothalamic Preautonomic Neurons, Carie R. Boychuk, Andrea Zsombok, Jeffrey G. Tasker, Bret N. Smith

Physiology Faculty Publications

Glucocorticoids rapidly regulate synaptic input to neuroendocrine cells in the hypothalamic paraventricular nucleus (PVN) by inducing the retrograde release of endogenous messengers. Here we investigated the rapid effects of dexamethasone (DEX) on excitatory synaptic input to feeding-related, preautonomic PVN neurons using whole-cell patch-clamp recordings. In ∼50% of identified gastric-related preautonomic PVN neurons, DEX elicited a biphasic synaptic response characterized by an initial rapid and transient increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), followed by a decrease in mEPSC frequency within 9 min; remaining cells displayed only a decrease in mEPSC frequency. The late-phase decrease in mEPSC frequency …