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Proteinogenic Brain Impermeant Amino Acid, Isovaline

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Proteinogenic Brain Impermeant Amino Acid, Isovaline ANTIALLODYNIA AND SURGICAL IMMOBILITY PRODUCED BY THE NON- PROTEINOGENIC BRAIN IMPERMEANT AMINO ACID, ISOVALINE by Ryan Arthur Whitehead B.Sc. (Honours), The University of British Columbia, 2007 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmacology & Therapeutics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2013 ©Ryan Arthur Whitehead, 2013 Abstract This thesis describes research stemming from investigation of the novel nonproteinogenic amino acid, isovaline. The first chapter is a background for the field of study. The second chapter investigates peripheral GABAB receptor-mediated mechanisms of action of isovaline, ɤ-aminobutyric acid (GABA), and baclofen. The third chapter details experimental evidence demonstrating that a combination of central hypnosis and peripheral analgesia produces general anesthesia. The fourth chapter describes the development and evaluation of a novel model of human trigeminal allodynia, a feature of intractable and severe pain in trigeminal neuralgia. The mechanism of action of isovaline, as for GABA and baclofen, was found involve peripheral GABAB receptors, revealed through attenuation of peripheral prostaglandin E2 (PGE2)-induced allodynia. This mechanism was tested by reversal of allodynia by the GABAB antagonist CGP52432 and potentiation of allodynia by the GABAB positive modulator CGP7930. Immunohistochemical staining showed confluence of GABAB1 and GABAB2 subunits on free nerve endings and keratinocytes. Peripherally administered isovaline and GABA produced analgesia but no CNS depression, whereas baclofen produced analgesia accompanied by pronounced sedation and hypothermia. In a forced exercise model of osteoarthritic dysfunction isovaline restored joint operability lost presumably due to knee pain. Next, we hypothesized that co-administration of a peripherally restricted analgesic with a central hypnotic (isovaline co-administered with propofol) would produce general anesthesia in mice. We first demonstrated that isovaline and fentanyl produced surgical analgesia without appreciable sedation. Propofol alone produced hypnosis without analgesia or surgical anesthesia. ii When administered with hypnotic doses of propofol, coadministration of isovaline resulted in general anesthesia. Under fixed ratio hypnotic and analgesic dose ratios, propofol-isovaline anesthesia had a markedly higher therapeutic index than propofol-fentanyl. When co- administered with a fixed hypnotic dose of propofol, isovaline in contrast to fentanyl did not have a maximum tolerated dose (MTD). Next we describe an intracisternal strychnine mouse model of human trigeminal neuropathic pain is described. The model reflects the efficacy of clinical drug treatments as morphine administered intraperitoneally was not effective, but intracisternally injected carbamazepine epoxide provided pain relief. Isovaline applied near the spinal trigeminal nucleus was effective in this model, validating its utility in detecting efficacy of novel analgesics. iii Preface My contributions to chapter two were undertaking the in vivo experiments, and the experimental design, analysis and the writing associated with it, and undertook the journal submission processes under supervision of Drs. Bernard MacLeod and Ernest Puil in the Hugill Centre for Anesthesia and Analgesia. The development of the manuscript was also subjected to significant collaborative advice from Drs. Schwarz and Ries. A version of chapter two has been published: Whitehead RA, Puil E, Ries CR, Schwarz SK, Wall RA, Cooke JE, Putrenko I, Sallam NA, MacLeod BA. GABA(B) receptor-mediated selective peripheral analgesia by the non- proteingogenic amino acid, isovaline. Neuroscience 213: 154-60, 2012. My contribution to chapter three was in the design, conducting, and analysing of experiments and writing associated with it. All experiments were undertaken in the Hugill Centre for Anesthesia and Analgesia. I wrote the manuscript and undertook the journal submission process, under supervision of Drs. Bernard MacLeod, Ernest Puil and Stephan Schwarz co-wrote the manuscript with me. A version of chapter is in preparation for peer-reviewed publication: Whitehead, R.A., Puil, E., Ries, C.R., Schwarz S.K., Fung, T., MacLeod, B.A. Isovaline co- administered with propofol produces general anesthesia in mice. In preparation for submission, 2013. My contribution to the fourth chapter was in the design, validation of experimental procedures, and analysis of experiments and writing of the manuscript. All experiments were undertaken in the Hugill Centre for Anesthesia and Analgesia. Drs. Bernard MacLeod, Ernest Puil and Stephan iv Schwarz co-wrote the manuscript with me. I also contributed, through review of experimental data, blind re-evaluation of data transformed to a new non-parametric allodynia score system, re- analysis of data including new statistical approaches. I wrote the manuscript in collaboration with Drs. MacLeod, Puil and Schwarz and undertook the journal submission process. A version of chapter four has been pubished: Lee IO, Whitehead RA, Ries CR, Schwarz SK, Puil E, MacLeod BA. Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia. Can J Anaesth [Epub ahead of print], 2013. v Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iv Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ ix List of Figures .................................................................................................................................x List of Abbreviations ................................................................................................................... xi Acknowledgements ..................................................................................................................... xii Dedication ................................................................................................................................... xiii Chapter 1: General Introduction .................................................................................................1 1.1 Scope of thesis ................................................................................................................ 2 1.2 Background ..................................................................................................................... 5 1.2.1 Definitions of pain, allodynia and hyperalgesia ......................................................... 5 1.3 Ascending pain pathways ............................................................................................... 7 1.3.1 Neospinothalamic tract ............................................................................................... 9 1.3.1 Paleospinothalamic tract ........................................................................................... 10 1.3.1 Archispinothalamic tract ........................................................................................... 11 1.4 Translational pain testing preparations in vivo ............................................................. 11 1.4.1 Tail-flick assay .......................................................................................................... 12 1.4.2 Acute chemical pain .................................................................................................. 13 1.4.3 Chronic pain .............................................................................................................. 15 1.4.4 Osteoarthritis ............................................................................................................ 16 1.4.5 Models of allodynia .................................................................................................. 18 1.4.6 Tourniquet intravenous regional analgesia ............................................................... 19 1.5 Analgesics, inhibitory amino acids and their receptors ................................................ 21 1.5.1 Non-steroidal anti-inflammatory drugs..................................................................... 22 1.5.2 Opioids ...................................................................................................................... 23 1.5.3 Gabapentinoids ......................................................................................................... 24 1.5.1 Glycine ...................................................................................................................... 26 1.5.2 γ-aminobutyric acid (GABA) ................................................................................... 28 1.5.3 GABAA receptors ...................................................................................................... 28 1.5.3 GABAB receptors ...................................................................................................... 29 1.5.3 Isovaline ...................................................................................................................
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