The Effects of Tonic Muscle Pain on the Sympathetic and Somatic Motor Systems in Human
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The Effects of Tonic Muscle Pain on the Sympathetic and Somatic Motor Systems in Humans Azharuddin Fazalbhoy A thesis in fulfillment of the requirements for the degree of Doctor of Philosophy Prince of Wales Clinical School Faculty of Medicine January 2014 ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed ................................................................. Date .......22/01/2014........................................ ii PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Fazalbhoy First name: Azharuddin Other name/s: Abbreviation for degree as given in the University calendar: PhD School: Prince of Wales Clinical School Faculty: Medicine Title: The effects of tonic muscle pain on the sympathetic and somatic motor systems in human Abstract 350 words maximum: (PLEASE TYPE) Mechanisms underlying the development of chronic muscle pain in humans remain unknown. Our current understanding is based on experimentation in animals, which has resulted in a multitude of theories to postulate the mechanisms in humans. The vicious cycle theory – a popularised but unsupported theory in humans – suggests that muscle metabolites produced by static muscle contractions stimulate group III and IV muscle nociceptors leading to an excitation of gamma-motoneurons through a reflex mechanism. Increased gamma-motor drive causes intrafusal fibres to contract increasing muscle spindle afferent firing. This activity in turn will raise the activation level in the pool of alpha-motorneurones projecting to the primary muscle increasing resting muscle tonus. Muscle spindle afferents and postganglionic sympathetic outflow to skin and muscle was recorded from healthy subjects using the technique of microneurography. Cardiorespiratory function was measured non-invasively. Muscular pain was induced using a solution of hypertonic saline tonically infused via indwelling cannulae delivered by an infusion pump. The rate of infusion was controlled to ensure subjects experienced mild to moderate pain. Muscle spindle afferents fail to show any change in spontaneous discharge rate in response to tonic muscle pain contradicting the observations and conclusions from animal studies. Sympathetic outflow to skin demonstrated a transient increase followed by a sustained decrease during infusion of hypertonic saline. Sympathetic outflow to muscle demonstrated a dichotomy of responses during muscle pain: half of the subjects showing increasing sympathetic activity, BP, and HR; whilst the others showed decreasing sympathetic activity, BP, and HR. Consistent responses were seen in the same individuals when the study was reproduced in a second recording. This investigation clarifies our understanding of the physiological consequences tonic pain has on sympathetic outflow and muscle spindle afferents in the context of developing chronic muscle pain. There is no apparent evidence to suggest that tonic pain increases the discharge rate of spontaneously active muscle spindle afferents to result in chronic muscle pain as proposed by the “vicious cycle” theory. There is, however, evidence of sustained changes in sympathetic outflow to muscle and skin in response to tonic pain that may contribute to the development of chronic pain. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). .................................................................... .............................................................. .....22/01/2014........................ Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS iii ACKNOWLEDGEMENTS I am in tears as I write this. This PhD thesis marks the end of a long journey I began 11 years ago after graduating from high school. It was a difficult time for me, but only a few days after starting university I promised myself to turn it around and aim to achieve excellence. I’ve had tremendous amounts of support along the way; hence, I would like to dedicate this thesis to my family. To my wife Farzana, the last 18 months have been a tremendous struggle for both of us. I cannot thank you enough for your love, patience, and support during this time. I know at times I have been very demanding and unpleasant to be around. Thank you so much for understanding and being patient as I spent countless hours at Neura and at home trying to finish this PhD. I would not have finished this if it weren’t for your support and encouragement. No longer will we spend weekends at home so that I can finish my work. From now on it will be just you and I. To my parents Papa and Mummy, you have by far been my greatest support throughout this journey. You sacrificed everything you had and everything you knew to come to a foreign land and start a new life with only one vision that your children get a good education. I hope I have lived up to your expectations and made you proud by achieving the highest form of tertiary education. There is nothing in this world that I could ever give you that will equate to the amount of love and support you have given me. I make dua that it all comes back to you. To my brother Faris, you have been my greatest inspiration in completing this journey. From my first day at university you have been extremely pushy about me being as motivated, dedicated, and hard working as you are. The pressure was relentless and there were times when you just simply got on my nerves, but I am so grateful that you did because if it weren’t for that pressure I may not be where I am today. Thank you so much for everything you have done for me. Also, thank you to my sister in-law Aliya and my little nephew Zeyaan, cha cha has a PhD now. iv To my lab colleagues Elie, Rania, Cheree, and Rachael, thank you so much for all your help running experiments and more importantly for your friendship. We’ve had the most amazing times together in the lab and at conferences, which simply would not have been the same without you all. I wish you all the best with your future and hope that we can continue our friendship long until we are old and miserable. To my supervisor Ingvars, I am truly grateful for what you have taught me about being a good scientist. Your high standards of scientific research, critical evaluation, and constructive criticism are something to be envious of. Yes, at times they have been over the top and frustrating but I have nothing but respect for you as these qualities have certainly influenced me and have given me a foundation which I believe will give me great success in a career of research. I also thank you for your friendship and support especially in the first 12 months of my PhD. There were times when you literally had to spoon-feed me, but never did you make me feel as if I couldn’t knock on your door and ask for help. Last but not least I would like to thank my supervisor Vaughan, there are simply no words in the English language that can express my gratitude for what you have done for me. I approached you to do a PhD with nothing except a little enthusiasm and motivation and you have helped turn it into a reality. Thank you so much for your advice, your help, your time, and your friendship. I couldn’t have asked for a better PhD supervisor. You truly have made my time as a PhD student an absolute delight. All I can say is when I grow up I want to be like you. v ABSTRACT Mechanisms underlying the development of chronic muscle pain in humans remain unknown. Our current understanding is principally based on experimentation in animals, which has resulted in the formulation of a multitude of theories and physiological models to postulate these mechanisms in humans. The vicious cycle theory – a popularised but unsupported theory in humans – suggests that muscle metabolites produced by static muscle contractions stimulate group III and IV muscle nociceptors leading to an excitation of gamma-motoneurones through a reflex mechanism. Increased gamma-motor drive causes intrafusal fibres to contract increasing muscle spindle afferent firing.