Relationship between pain and anxiety in rats [Elektronische Ressource] / Kerstin Röska

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Sujets

• Biologie

Informations

• Publié par: johannes_gutenberg-universitat_mainz
• Publié le: 01 janvier 2009
• Nombre de lectures: 8
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Relationship between pain and anxiety in rats





Dissertation

Zur Erlangung des Grades

„Doktor der Naturwissenschaften“




am Fachbereich Biologie

der Johannes Gutenberg-Universität

in Mainz




Kerstin Röska

Geb. am 19. September 1980 in Ochsenfurt





Baden Baden, 17. November 2009






























Tag der mündlichen Prüfung: 3. November 2009
2 Röska K. Relationship between pain and anxiety in the rat Index
SUMMARY 5
INTRODUCTION 7
Pain- a sensory and emotional experience 7
Neuroanatomy of pain 7
Mechanisms and pathophysiology of pain 9
Signs and symptoms 11
Treatment of neuropathic pain 12
Animal models for neuropathic pain 13
Assessment of pain in animals 15
Anxiety – a particular form of stress 16
Neuroanatomy of anxiety 17
Pathophysiology of anxiety disorders 17
Treatment of anxiety 19
Models to detect anxiety-related behaviour 20
Link between pain and anxiety 20
Amygdala modulates emotion and pain 22
Vasopressin 23
Oxytocin 24
Aim of the study: 26
MATERIALS AND METHODS 28
Animal care 28
Low anxiety and high anxiety behaviour rats 28
Surgeries 28
Chronic constriction injury (CCI) and partial nerve injury (PNL) of the sciatic nerve 28
Microinjection in amygdala (insertion of cannula) 29
Histological verification of the injection site 29
Behavioural tests 30
Measurement of mechanical hypersensitivity 30
Motility test – activity box 30
Anxiety test – elevated plus maze 30
Pharmacologically induced anxiety 31
Quantitative real-time polymerase chain reaction (Taqman RT- PCR) 31
Drugs and anaesthetics 32
Statistics and design of experiments 32
Dropouts: 34
CHAPTER I 36
Anxiety-like behaviour in animals with mononeuropathy is reduced by the analgesic
drugs morphine and gabapentin 36
Pain induces anxiety in rats with sciatic nerve injury 37
Effect of midazolam, morphine and gabapentin on mechanical hypersensitivity 39
Midazolam, morphine and gabapentin reduce pain-induced anxiety 40
Discussion 43
CHAPTER II 47
Effect of several drugs on pain-induced anxiety-like behaviour 47
8-OH-DPAT 51
R-715 52
SSR240612 52
Tramadol 52
Lacosamide 53
Mexiletin 53
Discussion 54
3 Röska K. Relationship between pain and anxiety in the rat Index
CHAPTER III 61
Role of oxytocin and vasopressin in pain-induced-anxiety in rats with sciatic nerve
lesion 61
Oxytocin is upregulated in the amygdala of rats with neuropathic pain 63
Effect of oxytocin antagonist on mechanical hypersensitivity 64
Effect of oxytocin antagonist on pain-induced anxiety-like behaviour 64
Vasopressin is upregulated in the amygdala of rats with neuropathic pain 66
Effect of vasopressin on mechanical hypersensitivity 67
Effect of vasopressin on pain-induced anxiety-like behaviour 67
Discussion 68
CHAPTER IV 72
Effect of pre-existing anxiety on the development of neuropathic pain in rats 72
Characterisation of high and low anxiety-like behaviour in the two strains 73
Different levels of mechanical hypersensitivity in HABs and LABs with sciatic nerve lesion 73
Anti-nociceptive effect of gabapentin in HAB and LAB rats with sciatic nerve injury 74
Discussion 77
CHAPTER V 82
Effect of pharmacologically induced state anxiety on mechanical hypersensitivity 82
Effect of sub-chronic PTZ treatment on hypersensitivity and anxiety-like behaviour 84
Effect of gabapentin on PTZ-induced mechanical hypersensitivity and anxiety-like behaviour 86
Effect of midazolam on PTZ-induced mechanical hypersensitivity and anxiety-like behaviour 87
Discussion 89
SUMMARY AND GENERAL DISCUSSION 94
REFERENCE LIST 103
LIST OF ABBREVIATIONS 120
APPENDIX 122
CURRICULUM VITAE 123
AFFIRMATION 126
4 Röska K. Relationship between pain and anxiety in the rat Summary
SUMMARY
Clinically, it is well known that neuropathic pain often induces comorbid symptoms
such as anxiety. In turn, also anxiety has been associated with a heightened
experience of pain. Although, the link between pain and anxiety is well recognized in
humans, the neurobiological basis of this relationship remains unclear. Therefore, the
aim of the current study was to investigate the influence of neuropathic pain on
anxiety and vice versa in rats by assessing not only pain-related behaviour but also
by discovering possible key substrates which are responsible for the interrelation of
pain and anxiety.
In rats with a chronic constriction of the sciatic nerve (CCI model) anxiety-like
behaviour was observed. Since anxiety behaviour could be completely abolished
after the treatment of the pure analgesic drugs gabapentin and morphine, we
concluded that anxiety was caused by the strong persistent pain. Furthermore, we
found that the neuropeptides oxytocin and vasopressin were upregulated in the
amygdala of CCI rats, and the intra-amygdala treatment of an oxytocin antagonist but
not the vasopressin antagonist could reduce anxiety-like behaviour in these animals,
while no effect on mechanical hypersensitivity was observed. These data indicate
that oxytocin is implicated in the underlying neuronal processes of pain-induced
anxiety and helps to elucidate the pathophysiological mechanisms of neuropathic
pain.
To assess the influence of trait anxiety on pain sensation in rats, we determined
mechanical hypersensitivity after sciatic nerve lesion (CCI) in animals selectively bred
for high anxiety or low anxiety behaviour. The paw withdrawal thresholds were
significantly decreased in high anxiety animals in comparison to low anxiety animals
2 and 3 weeks after surgery. In a second model state anxiety was induced by the
sub-chronic injection of the anxiogenic drug pentylentetrazol in naive rats. Pain
response to mechanical stimuli was increased after pharmacologically-induced
anxiety. These results provided evidence for the influence of both trait and state
anxiety on pain sensation.
The studies contribute to the elucidation of the relationship between pain and anxiety.
We investigated that the neuropathic pain model displays sensory as well as
emotional factors of peripheral neuropathy. Changes in expression levels of
5 Röska K. Relationship between pain and anxiety in the rat Summary
neuropeptides in the central nervous system due to neuropathic pain may contribute
to the pathophysiology of neuropathic pain and its related symptoms in animals which
might also be relevant for human scenarios. The results of the current study also
confirm that anxiety plays an important role in the perception of pain.
A better understanding of pain behaviour in animals might improve the preclinical
profiling of analgesic drugs during development. The study highlights the potential
use of the rat model as a new preclinical tool to further investigate the link between
pain and anxiety by determining not only the sensory reflexes after painful stimuli but
also the more complex pain-related behaviour such as anxiety.
6 Röska K. Relationship between pain and anxiety in the rat Introduction
INTRODUCTION
Pain- a sensory and emotional experience
Pain is a sensory perception which is defined by the International Association for the
Study of Pain (IASP) for clinical and scientific purposes as “an unpleasant sensory
and emotional experience associated with actual or potential tissue damage or
described in terms of such damage” (143). The most important physiological function
of this subjective sensory system is warning the body to avoid tissue damage and
protect from painful and serious impairment.
Pain can be divided into two different modalities. While nociceptive pain occurs after
peripheral somatic or visceral tissue damage, neuropathic pain, which is the main
topic of this thesis, is defined as “pain, initiated or caused by a lesion or disease in
the somatosensory system” (214). During neuropathic pain state the original warning
function is lost, and the pain experience becomes manifested in chronic pain without
tissue damage.
A pain survey - performed in 16 European countries - showed that 19 % of European
population are suffering from chronic pain (29). In Germany about 14 million people
complain about strong and long-lasting pain, which often affects daily life activities,
quality of life and their effectiveness at work. Common types of chronic pain include
back pain, headaches, arthritis, cancer pain, and neuropathic pain, which results from
nerve injuries. Regardless of the type of chronic pain, the physical and emotional
effects can be devastating. Patients often report about associated comorbidities such
as depression, anxiety and sleep disturbances. Despite our understanding of
nociceptive processing and of plastic changes after persistent noxious input has
immensely increased within the last decades, neuropathic pain is stil