The effective treatment of chronic pain remains one of the major global health challenges of the 21 st century. Current treatment therapies available include the non-steroidal anti-inflammatory drugs (NSAIDS) e.g. ibuprofen and also opioid based compounds such as morphine sulphate (MST). These drugs have been very useful especially in treating post- operative acute pain states and pain associated with joint diseases such as osteoarthritis. Unfortunately, the long- term use of these drugs has been hampered by the reported unwanted physical side effects such as cardiovascular problems and gastrointestinal disorders, as well as the development of tolerance and addiction, which has made them very unattractive for the treatment of many chronic pain states. Thus, the need to identify new therapeutic targets and substrates for the treatment of chronic pain has become a major goal for pain scientists all over the world. The N-acylethanolamines (NAEs) are endogenous bioactive lipid compounds known to mediate a number of physiological effects including, but not limited to analgesia, through their interactions with a number of receptor systems, notably the inhibitory G-protein coupled cannabinoid receptors and the nuclear receptor peroxisome proliferator activated receptor (PPARα). Elevation in the physiological levels of these compounds, for example anandamide (AEA) and palmitoylethanolamide (PEA) have been shown to produce analgesic effects in animal models of both inflammatory and neuropathic pain, although the cellular and molecular mechanisms involved are not well understood. The physiological levels of NAEs are under tight regulation by hydrolytic enzymes such as fatty acid amide hydrolase (FAAH); as a result, their physiological effects are rather short-lived. Pharmacological inhibition of FAAH using selective inhibitors such as the carbamate compound, URB597, is emerging as a useful approach for overcoming this problem. Previous work in our group comparing the analgesic effects of acute and repeated pharmacological inhibition of F AAH using URB597 has shown that, acute rather than repeated inhibition of F AAH was effective in attenuating inflammatory pain behaviour. Furthermore, the magnitude of elevation in NAE levels was greater following acute treatment with URB597 compared with repeated treatment. These findings suggest that, compounds that target F AAH for the treatment of pain may not be very effective when give repeatedly, as would be the case when treating chronic pain states. The aim of this thesis is to understand the cellular and molecular mechanisms underlying the analgesic effects of NAEs, and also to identify molecular changes associated with both acute and repeated FAAH inhibition which may account for the difference in analgesic effects previously reported. Data presented here suggest that this difference in analgesic effects is not just down to changes in the EC system since both acute and repeated inhibition of F AAH were associated with changes in N APE-PLD (N AE synthetic enzyme) protein expression, but also the ability of the treatment to modulate components of the inflammatory signalling cascade. Thus, I demonstrate here for the first time, that a mechanism underlying the analgesic effects of NAEs involves suppression of the induction of the pronociceptive cyclooxygenase (COX)-2 enzyme, possibly via the activation of the cannabinoid and/or PPARα receptor systems, in the carrageenan model of inflammatory pain. The modulation of COX-2 induction by the PPARα system was further demonstrated by local administration of the endogenous PPARα ligand, PEA into the hindpaw, which suppressed carrageenan-induced COX-2 protein expression as well as protein expression of inducible nitric oxide synthase (iNOS), which also plays a role in the development of inflammatory hyperalgesia. The role of PPARα (a receptor target for some NAEs), as a potential therapeutic target for the treatment of chronic pain states such as neuropathic pain was studied in the rat spinal nerve ligation (SNL) model of neuropathic pain. Systemic administration of the synthetic PPARα ligand, WYI4643, was associated with a rapid decrease in neuronal responses in SNL, but not sham-operated, rats. Taken together these findings suggest that targeted modulation of NAEs could provide a means of activating multiple receptor systems, and consequently offers a unique therapeutic window of opportunity to develop broad-spectrum and robust analgesic drugs that could be used to effectively treat chronic pain.

Chronic pain is a highly unmet clinical need; often treatment is only partially effective, and is frequently accompanied by unpleasant side effects. The voltage-gated sodium channel Nav1. 7 has emerged as an attractive target in the treatment of pain. Expressed preferentially in nociceptive DRG neurons, Nav1.7 functions at the plasma membrane to transmit peripherally generated pain signals towards the central nervous system. Manipulating Nav1.7 trafficking mechanisms to reduce the cell surface density of the channel is thus a promising approach to reduce the sensation of pain, yet there are no previous reports on Nay1.7 trafficking mechanisms. To allow investigation of human Nav1.7 trafficking mechanisms, epitope tags were inserted into the extracellular domains of the channel. Tagged channels expressed within the cells, but lacked surface expression when assayed by immunostaining. chemiluminescence assays and electrophysiology. Studies then focussed on the role of individual cytosolic domains of Nav1.7 - which harbour a number of consensus trafficking motifs- in the trafficking of the channel. Peptide domains of Nav1.7 were employed in a peptide competition assay to screen the domains for a dominant negative effect on the trafficking of the channel. Results from these assays were inconclusive. Internalisation of the full-length channel was demonstrated using a surface biotinylation assay. Chimeras of C04 and three of the cytosolic domains of Na,,1.7 were constructed to investigate the underlying mechanism of channel endocytosis. Using immunostaining assays, all three domains were shown to promote internalisation of C04, consistent with the presence of consensus endocytosis motifs in each. Furthermore, the Na,,1.7-C-terminal-CD4 chimera was shown to co-Iocalise with markers of early endosomes following endocytosis. These data provide the first evidence of endocytosis of Na.,.1.7 and have implicated a role for the cytosolic domains of the channel in regulating this process. Further elucidation of these mechanisms could reveal novel targets for the treatment of pain.

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The aim of this thesis was to develop a new module on pain and discomfort to be used in conjunction with the UK World Health Organisation Quality of Life Assessment (WHOQOL-lOO) that elaborates the experience of chronic pain (CP). Further aims were to elucidate its psychometric properties and assess the quality of life (QoL) of people with CP. The WHOQOL-lOO is a multilingual, generic instrument for the subjective assessment of QoL in adults. It contains 100 core items represented by 25 specific facets covering six broad domains. The four items in the WHOQOL-lOO that address pain and discomfort have been found to under-represent the impact of pain on QoL, hence the need to develop a pain and discomfort module (PDM). Focus groups (FG's) were conducted to generate data on how pain affects QoL. Ten new facets of QoL pertaining to CP were identified; flare-ups; pain relief; anger/frustration; vulnerability/fear/worry; uncertainty; loss/loneliness/feeling alone; positive strategies; communication; guilt/burdening others; relationship with health care providers. Concurrently, a web survey was conducted to provide confirmation and validation of the areas of QoL identified. A definition and items were written for each new facet of QoL. The resulting 108-item questionnaire was pre-piloted in a sample of people with CP using the technique of cognitive interviewing. Following deletion and modification of items, the 68-item PDM and 16 importance items were administered in a cross-sectional survey, where 4 facets remained in the PDM represented by 16 items. The WHOQOL and PDM were administered to low back pain patients having lumbar epidural steroid injections at baseline and 4-weeks following the intervention in a longitudinal survey to examine sensitivity to change. Patients not undergoing treatment also completed the WHOQOL and PDM at baseline and after 2 weeks to examine test-retest reliability. Pain relief, anger and frustration, vulnerability, fear and worry and uncertainty influence the QoL of people with pain. The PDM will be self-administered and must be used in conjunction with the UK WHOQOL-lOO for large-scale survey work, for evaluating the effectiveness of new and existing interventions designed to reduce the impact of pain on QoL and to identify the needs of sufferers.

Substantial evidence has accumulated for the involvement of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral/chronic pain. Notably, poorly brain-penetrating glycinceB NMDA antagonists were particularly potent in in vivo models of inflammatory visceral pain. The aim of this thesis was to further investigate the pharmacology of peripheral, compared to central, NMDA receptors.

Symptoms which are experienced in the absence of a clear biomedical diagnosis, after appropriate investigation are commonly labelled as 'functional', A theoretical model encompassing functional pain and conversion disorder within a framework of 'auto- suggestive disorder' provides the starting point for the studies reported here. Direct hypnotic suggestion of increasingly painful heat was used to produce an experience of truly 'functional' pain in a group of highly hypnotisable participants, judged to be similar to an experience of 'real' physically-induced pain. This result was supported using functional imaging, demonstrating similar patterns of neural activation in response to physically-induced and hypnotically-induced pain. This study is the first to demonstrate specific neural activity associated with a functional pain experience in healthy controls. Hypnotic and non-hypnotic suggestion was used to modulate the pain experienced by a group of fibromyalgia patients, a condition considered by many to be a functional disorder. Manipulation of such pain in this way enabled the direct observation of the neural activity underlying fibromyalgia pain, circumventing the 'baseline problem' common to neuroimaging investigations of chronic pain. The results linked specific regional activity in areas of the pain matrix with the modulation of fibromyalgia pain. The hypnotic susceptibility of a cohort of fibromyalgia patients was assessed and compared with a group of control participants. No significant differences in hypnotic susceptibility scores were observed, failing to confirm the auto-suggestive disorder hypothesis that these patients should score higher than controls. The findings presented here do not directly support the classification of functional pain conditions as auto-suggestive disorders. However, they do demonstrate for the first time the neural activity associated with the production of a truly functional pain. They provide support for the existence of a central pattern generator for pain, a mechanism capable of generating the experience of pain in the absence of nociceptive input.

In an attempt to bridge the widely acknowledged gap between research and clinical practice, this thesis examined the feasibility of benchmarking outcomes for published psychological treatments of chronic pain for application within routine clinical settings. Benchmarking outcomes is relatively common for psychological treatments in the mental health field, but in spite of the prevalence of chronic pain and its known impact on many areas of functioning, the chronic pain literature has previously only considered the generic application of benchmarks for developing services and considering standards for waiting times. Four studies of mixed methodological approaches were conducted. The first aimed to ascertain the extent of similarities between published psychological treatments of chronic pain and treatments delivered in routine clinical settings. This was to ensure that the application of benchmarks from the published literature to routine clinical settings would be meaningful. The second study examined whether the published literature was likely to facilitate the development of benchmarks, and the third sought clarification in terms of outcome domains within which useful benchmarks could be generated. The final study was a meta-analysis of data extracted from the published literature within specified outcome domains. The results suggested that it would be meaningful to apply benchmarks produced from the published literature to routine clinical settings, and that the literature would facilitate the development of benchmarks within several outcome domains. The meta-analysis led to the generation of four benchmarks. These were in the outcome domains of pain experience and physical functioning when compared with waiting list controls, and coping and cognitive appraisal and emotional functioning when compared with active controls. The impact of the design of each study and properties inherent within the literature on the benchmarks generated and their application within routine clinical settings was then considered, prior to suggestions for future research and clinical applications.

This research investigated interoceptive exposure as a treatment option for disabling pain-related fear. Interoceptive exposure was conceptualised as an extension of the Fear Avoidance Model and a literature review highlighted three important areas: attention/hypervigilance to pain and its threat value, fear-avoidance and the acceptance of pain. A treatment manual was developed based on a literature review and an elaborated single case experimental design methodology was used to determine treatment efficacy. Seven participants were recruited and four completed treatment which was designed as an ABC sequence: A, baseline; B, education; C interoceptive exposure. Follow up data were obtained at three months post-treatment. Data were obtained from psychometrically standardised assessments, daily measures of the treatment target, and sessional process measures. Participants completed a post-treatment Change Interview in an attempt to evaluate treatment causality in a non-biased way. There was variation on the standard measures; all of the participants made significant changes on some but not all of the measures. Target measures showed both variation and stability. Process measures showed that all of the participants could engage in the treatment exercises. The participants rated the treatment as being fairly logical however there was differences in expectations about how successful the treatment would be. At the Change Interview, all of the participants described changes which they stated were important and unlikely to occur without therapy. There is some evidence at different levels that this treatment may be effective. A combination of attention, fear-avoidance and acceptance of pain treatment approach has not been used before and this research indicates promising results for those suffering with chronic pain. However further research is necessary. The procedure could be refined; interoceptive exposure could be explored in more depth and pain and avoidance behaviour could be considered in relation to other goals.