chronic pancreatitis, pain, and anxiety in an alcohol and high fat mouse model

132 Pages·2016·1.69 MB·English

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Theses and Dissertations--Gerontology College of Public Health
2016
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Tiffanie Clinkinbeard
University of Kentucky, [email protected]
Digital Object Identifier: http://dx.doi.org/10.13023/ETD.2016.247
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Clinkinbeard, Tiffanie, "CHRONIC PANCREATITIS, PAIN, AND ANXIETY IN AN ALCOHOL AND HIGH FAT
MOUSE MODEL" (2016). Theses and Dissertations--Gerontology. 9.
https://uknowledge.uky.edu/gerontol_etds/9
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The document mentioned above has been reviewed and accepted by the student’s advisor, on
behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of
the program; we verify that this is the final, approved version of the student’s thesis including all
changes required by the advisory committee. The undersigned agree to abide by the statements
above.
Tiffanie Clinkinbeard, Student
Dr. Karin Westlund High, Major Professor
Dr. John F. Watkins, Director of Graduate Studies
STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are
my original work. Proper attribution has been given to all outside sources. I understand
that I am solely responsible for obtaining any needed copyright permissions. I have
obtained needed written permission statement(s) from the owner(s) of each third party
copyrighted matter to be included in my work, allowing electronic distribution (if such
use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as
Additional File. I hereby grant to The University of Kentucky and its agents the
irrevocable, non-exclusive, and royalty free license to archive and make accessible my
work in whole or in part in all forms of media, now or hereafter known. I agree that the
document mentioned above may be made available immediately for worldwide access
unless an embargo applies. I retain all other ownership rights to the copyright of my
work. I also retain the right to use in future works (such as article or books) all or part of
my work. I understand that I am free to register the copyright to my work.

REVIEW, APPROVAL AND ACCEPTANCE
The document mentioned above has been reviewed and accepted by the student’s advisor,
on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on
behalf of the program; we verify that this is the final, approved version of the student’s
thesis including all changes required by the advisory committee. The undersigned agree
to abide by the statements above.
Tiffanie Clinkinbeard, Student
Dr. Karin Westlund High, Major Professor
Dr. John Watkins, Director of Graduate Studies
CHRONIC PANCREATITIS, PAIN,
AND ANXIETY IN AN ALCOHOL

AND HIGH FAT MOUSE MODEL

_______________________________________

DISSERTATION
_______________________________________

A dissertation submitted in partial fulfillment of
the requirements for the degree of Doctor of

Philosophy in Gerontology at the University of
Kentucky

By

Tiffanie Clinkinbeard

Lexington, KY

Co-Directors: John F. Watkins, Professor of Gerontology and
Karin Westlund High, Professor of Physiology

Copyright © Tiffanie Jane Clinkinbeard, 2016
ABSTRACT OF DISSERTATION

CHRONIC PANCREATITIS, PAIN, AND ANXIETY IN AN ALCOHOL AND HIGH
FAT MOUSE MODEL

Homeodynamic space (HDS) shrinks as vulnerability increases with aging and
repeated damage to the cells. HDS is lost in alcoholic pancreatitis patients due to
overconsumption of alcohol, smoking, and high fat diets. Etiologically relevant animal
models for study of chronic pancreatitis (CP) are needed. In order to begin filling this gap
a central purpose of this dissertation research was to examine relationships between the
alcohol and high fat diet (AHF) and pancreatitis with attention to hypersensitivity and
anxiety-like behaviors. The AHF diet induced pancreatitis described here etiologically
mimics human risk factors of AHF consumption for advancement to alcoholic CP.
In this study one group of mice was fed long term with a diet of high fat and
alcohol for comparison with a group fed normal chow. Mice consumed a liquid diet
containing 6% alcohol and a high fat supplement ad libitum over a period of five months.
Each group was evaluated for heat and mechanical hypersensitivity, and histology
indicative of CP.
The association of pancreatitis pathology with anxiety has been understudied.
Anxiety, like pain, is useful as a transient state but when anxiety is prolonged it is termed
a disorder. Anxiety is often comorbid with pain and depression. Therefore, it is important
to determine anxiety in mice with CP histology.
This model was characterized for the interaction of pancreatitis histology, as well
as persisting pain-, anxiety-, and fear-like behaviors. The AHF diet mice developed
hypersensitivity, demonstrated anxiety-like behaviors, and showed concurrent histology
consistent with CP. Nontransgenic mouse models where pancreatitis is induced only by a
combination of ad libitum liquid food with added alcohol and lard supplementation do
not currently exist, nor has an in-depth study of anxiety-like behaviors been conducted in
this mouse model. This dissertation research addresses this knowledge gap.
KEYWORDS: Pain, Pancreatitis Mouse Model, Anxiety, Alcohol, High Fat, Fear
Tiffanie Clinkinbeard
Student’s Signature
May 20, 2016
Date
CHRONIC PANCREATITIS, PAIN, AND ANXIETY IN AN ALCOHOL AND HIGH
FAT MOUSE MODEL

By

Tiffanie Clinkinbeard

Karin Westlund High, PhD
Co-Director of Dissertation

John F. Watkins, PhD
Co-Director of Dissertation

John F. Watkins, PhD
Director of Graduate Students

May 20, 2016
Date Signed
DEDICATION

To my family
ACKNOWLEDGEMENTS
This dissertation would not have been possible without the support and guidance
of a number of individuals. I first want to thank my dissertation committee, Drs. Karin
Westlund, John Watkins, Steven Estus, and William Stoops, as well as Dr. Brian Noehren
who served as my outside examiner. I especially want to recognize and acknowledge the
efforts of my dissertation co-chairs Dr. Westlund High and Dr. Watkins. First, Karin
Westlund High who provided resources and expertise integral to the research. Second,
John Watkins, who challenged me intellectually and pushed my thinking to a much
higher level. Each committee member provided insight and direction needed to complete
the dissertation research.
I also need to acknowledge the encouragement that I received from my friends
and family. My husband, David Clinkinbeard, sacrificed his time and supported me
through all aspects of the process, he helped my dreams come true in so many ways. My
parents Carl and Norma Dalton, and my brother Donald gave me the strength to
persevere through the difficult times. Thank you for being there for me and giving me the
freedom I needed to complete my work. Throughout my time at the University of
Kentucky I made many friends in both the Center for Gerontology and the Department of
Physiology. I want to thank these and other friends for counseling with me and cheering
me on throughout the process.

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TABLE OF CONTENTS
Acknowledgements……………………………………………………………..………..iii
Table of Contents…………………………………………………………………………iv
List of Tables...…………………………………………………………………………....x
List of Figures....………………………………………………….………………………xi
Chapter One: Introduction and Background
1 Introduction……………………………………………………………………………...1
2 Purpose……………….……………………………………………………………….....5
3 Specific Aims…………………………………………………………………………....5
3.1 Specific Aim 1: AHF Induced Chronic Pancreatitis Mouse Model ………….5
3.2 Specific Aim 2: Anxiety- and Fear-like Behavior in the AHF Chronic
Pancreatitis Mouse Model……….…………………………………………....…...6
4 Background….………………………………………………………………………..…6
4.1 Pain Sensing……………………………………………………………….6
4.1.1 Cutaneous Pain Sensing………...……………………………..6
4.1.2 Fiber Type and Sensing……………………………………….7
4.1.3 Acute Pain……………………………………………………..7
4.1.4 Peripheral Sensitization……………………………………….8
4.1.5 Central Sensitization…………………………………………..8
4.2 Chronic Pain and Health……….………………………………………….8
4.2.1 Chronic Pain…...…….………………………………………..8
4.2.2 Homeodynamics and Homeostasis.…………….……………10
4.2.3 Homeodynamic Space and Pancreatitis.……………………..11
4.2.4 Human Adaptation to the Loss of Homeodynamic Space..….12
4.3 Social Aspects of Alcoholic Chronic Pancreatitis…..…………………...13
4.4 Chronic Pancreatitis…………………...………………………………....14
4.4.1 Classification of Pancreatitis by Etiology..…………………..14
4.4.2 Physiology of Chronic Pancreatitis ………………………….16
4.4.3 Epidemiology of Chronic Pancreatitis……………………….20
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