Lillywhite, Amanda
(2020)
An investigation of the influence of co-morbid anxiety on functional connectivity changes in the MIA model of OA pain.
PhD thesis, University of Nottingham.
Abstract
Background:
Pain, although universally experienced and adaptive, can negatively impact daily functioning and quality of life when it becomes chronic. Osteoarthritis is one of the most commonly experienced chronic pain conditions, with a huge personal and societal impact. The treatment of OA can be challenging and is complicated by a number of frequently experienced co-morbid conditions.
Anxiety is often co-morbid in chronic pain conditions, including OA. Co-morbid anxiety is associated with an increase in levels of pain, an increased need for medication and worse outcomes after treatment than patients without these co-morbidities, particularly with opioids. The investigation of how anxiety mediates pain and responses to treatment, and the brain changes that occur in response to co-morbid anxiety and pain is still unclear. This thesis hypothesised that animal models of OA pain are associated with changes in functional connectivity in the brain, and anxiety exacerbates OA pain via alterations in these pathways and changes in endogenous opioid receptor tone.
Objectives:
1) To validate methods for measuring alterations in spontaneous fluctuations in the BOLD signal using resting-state fMRI in the rat.
2) To compare resting-state fMRI differences in the monosodium iodoacetate (MIA) model of OA in Wistar rats and Wistar-Kyoto rats, an inbred genetic strain which has a high anxiety behavioural phenotype.
3) To investigate to the potential contributions of alterations in opioid receptors and endogenous opioid tone in WKY rats and if this impacts upon the manifestation of pain behaviour in the model of OA.
Methods:
In this thesis, the Wistar-Kyoto inbred rat strain, which displays anxiety-related behaviour, was used with outbred Wistar rats as normal anxiety controls. Intra-articular administration of MIA (1mg) was used to model osteoarthritis pain in the knee.
fMRI was used to investigate resting-state functional connectivity changes in the two rat strains after intra-articular MIA, and ECoG was used to explore the temporal nature of neuronal activity. Medetomidine and isoflurane were used together to provide anaesthesia during these experiments.
Behavioural pharmacological studies were conducted to investigate responsiveness to morphine after intra-articular MIA in the WKY rats, and subsequently the endogenous opioidergic system was investigated through administration of naloxone.
Results:
The medetomidine and isoflurane anaesthetic regime was tested for the functional connectivity work and decided to be suitable for the study of resting-state fMRI in these rat models.
Functional connectivity differences were observed following induction of the MIA model of OA pain and correlation analysis revealed that the relationship between pain behaviour and functional connectivity from the vmPFC to S2/caudate putamen was altered in the high anxiety WKY strain of rats.
Using ECoG, increases in power of somatosensory evoked potentials, over the somatosensory cortex, were observed in response to noxious electrical stimulation after intra-articular MIA
Behaviourally, in the WKY rats, responses to morphine were attenuated, with increased endogenous opioidergic tone, suggesting that some of the differences in the sensitivity to morphine may reflect differences in the endogenous opioid system.
Conclusions:
The work in this thesis provided new evidence of the influence of anxiety on functional brain changes in the MIA model of OA pain, and possible involvement of the opioidergic system but further work is required to replicate the new functional connectivity data and focus on molecular mechanisms underpinning these alterations.
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