Thesis (Honors)--College of William and Mary, 2009. / Includes bibliographical references (leaves 21-24). Also available via the World Wide Web.

Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2009. / Full text also available online. Scroll down for electronic link.

L’utilisation des opioïdes est à l’origine de phénomènes de tolérance et d’hyperalgésie induite (HIO) aussi bien chez l’animal qu’en utilisation clinique. Ces phénomènes surviennent avec tous les opioïdes de manière dose-dépendante. Les mécanismes qui les sous-tendent sont complexes et imparfaitement connus. Le rémifentanil et le sufentanil sont les opioïdes les plus utilisés en France en anesthésie-réanimation. Leur utilisation s’accompagne d’une HIO qui majore la douleur postopératoire et peut être responsable de la persistance de la douleur à long terme. La perception des stimuli nociceptifs chez un patient sous anesthésie générale n’est pas aisée et repose encore sur des signes cliniques indirects d’activation du système sympathique. Ces signes peu sensibles et peu spécifiques conduisent à sous doser ou sur-doser les patients en opioïdes. Récemment, un nouvel outil de monitorage de la nociception est apparu, l’analgesia nociception index (ANI). L’ANI reflète le tonus parasympathique et de ce fait permettrait aux anesthésistes de mieux adapter le dosage des opioïdes. Dans cette thèse, nous avons d’abord évalué la sensibilité et la spécificité de l’ANI à détecter les stimuli nociceptifs, puis montré qu’elles étaient supérieures à celles des signes cliniques, et supérieures à d’autres indices de monitorage proposés. Ensuite nous avons validé la capacité de l’ANI à guider l’analgésie peropératoire du rémifentanil dans différentes situations.Sur le plan expérimental, nous avons exploré, après une exposition courte ou prolongée à différentes doses de rémifentanil et de sufentanil, les mécanismes associés à l’hyperalgésie thermique in vivo, chez la souris, et ex vivo, sur la voie des MAP kinases ERK1/2 et sur le trafic membranaire des récepteurs opioïdes de type µ (MOR) dans différentes cultures cellulaires. Chez la souris, nous avons mis en évidence une hyperalgésie précoce au saut sur plaque chaude, après exposition aux doses les plus élevées de rémifentanil, mais pas avec le sufentanil. De plus, nous n’avons pas observé d’HIO sur le léchage des pattes.Sur les cultures cellulaires, le rémifentanil comme le sufentanil activent la voie des MAPK ERK1/2 lors d’une exposition courte, avec apparition d’une désensibilisation lorsque l’exposition se prolonge. Le rémifentanil comme le sufentanil induisent une internalisation précoce et progressive des récepteurs MOR. / The use of opioids is associated with tolerance and induced hyperalgesia (OIH). Tolerance and OIH occur with all opioids and have been demonstrated both, in animals and in humans and are likely to be dose-dependent. The underlying mechanisms are complex and partially known. Remifentanil and sufentanil are the most used opioids in France in anesthesia and intensive care. Their use is associated with OIH that increases postoperative pain and may be responsible for persistent pain. In anesthetized patients, nociceptive stimuli are still detected according to clinical signs of sympathetic activation. These signs lack sensitivity and specificity and lead to underdosing or overdosing opioids. Recently, the analgesia nociception index (ANI), has been proposed as surrogate marker of nociception. The ANI reflects the parasympathetic tone and thus may allow anesthetists to better adapt the opioid dosage. In this thesis, we first evaluated the sensitivity and specificity of ANI to detect nociceptive stimuli, and showed that it better detects them than do clinical signs or than other currently available monitoring tools. Subsequently, we validated the ability of the ANI to adequately guide the intraoperative dosing of remifentanil in different clinical setting.After acute and sustained exposure to different doses of remifentanil and sufentanil we investigated, in vivo, the mechanisms associated with thermal hyperalgesia in mice, and ex vivo, the effect on the MAP kinase ERK1/2 pathway and the μ-type opioid receptor (MOR) membrane trafficking in human neuroblastoma and embryonic kidney cell cultures. In mice, high-dose remifentanil induced early hyperalgesia assessed by the jumping latency in a hot-plate test, but not the sufentanil. We did not observe OIH for the hind paw licking test. On cell cultures, after short exposure, both remifentanil and sufentanil produced activation of the MAP kinase ERK1/2 pathway, and rapid desensitization and internalization of the MOR.

Extracellular adenosin-5'-triphosphate (ATP) is an important signalling molecule. Cells of eukaryotic tissues release ATP and express responding purinergic receptors. Ionotropic P2X receptors are trimeric ion channels permeable for K+, Na+ and Ca2+ ions. Each subunit consists of two transmembrane domains (TM1 and TM2), an extracellular loop and intracellular N- and C- termini. The transmembrane region is formed by six helical domains. According to the known crystal structure of zfP2X4 receptor, TM1 helixes are oriented peripherally and stabilize TM2 helixes which form the ion gate. However, eletrophysiological studies revealed that TM1 might also participate in channel gating and forming of the ion pore in the open state. The aim of this work was to investigate the role of TM1 in the process of desensitization of rat P2X4 receptor using cystein-scanning mutagenesis. Mutation of two residues (in Asn32 and Tyr42) prolonged desensitization of P2X4 receptor. Moreover, experiments with a partial agonist α,β-methylenadenosin-5'-triphosphate (αβ-meATP) proved that conformation change of TM domains in the process of desensitization is independent on conformation change caused by an agonist binding. Conserved residue Tyr42 is located in the proximity of TM2 of neighbouring subunit. It probably interacts with Met336...

The use of relaxation, desensitization, and relaxation plus desensitization in the treatment of primary dysmenorrhea was investigated in this study. Subjects were 45 university women who experienced either congestive or spasmodic dysmenorrhea. Each subject was individually treated in four, one-hour sessions during the first 20 days of her menstrual cycle. Subjects were divided into three groups: Group 1 obtained four hours of progressive relaxation training, group 2 was asked to self-relax while being administered scenes from a standardized menstrual hierarchy, and group 3 obtained both relaxation training and desensitization. Type of dysmenorrhea was assessed by the Menstrual Symptom Questionnaire (MSQ). Symptom intensity and duration were assessed by the Retrospective Symptom Scale, the Menstrual Semantic Differential, the Menstrual Activities Scale, and the Menstrual Behavior Scale, and were administered pre-test, posttest, and three-month follow-up. Skin temperature during session 4 was obtained to evaluate the level of relaxation. Differences among treatment groups were analyzed using a one-way analysis of variance. t-tests for correlated samples were used to analyze within group changes form pretreatment to posttreatment. Results suggest all three treatments to be equally effective in reducing symptoms, negative attitudes, pain mitigating behaviors, and invalid hours. Symptom relief was not associated with skin temperature increases. The possibility of placebo playing a role in these results cannot be ruled out. Finally, the division of primary dysmenorrhea into spasmodic and congestive types by the MSQ is inaccurate, most probably due to the confounding nature of the scoring system.

No / Recent research addressing the use of music to support the needs of people receiving treatment for drug addiction has led to the development and implementation of music-assisted therapeutic interventions. We hypothesized that two different music modalities combined with systematic desensitization can counter-condition drug-related cues and significantly reduce the associated craving responses. We further examined the effect of the two treatments on cognitive and psychopathological components of addiction. Twenty-four individuals experiencing drug addiction were randomly assigned to one of the three study groups, namely systematic desensitization (SD) combined with listening to New Age meditation music improvised live on Tibetan bowls (IMT), systematic desensitization combined with listening to relaxing New Age music recorded in individual MP3 devices (NIMT), or a control group that received no additional therapeutic intervention (CTR). Participants in the two treatment groups received six sessions in addition to their standard treatment during a period of three weeks. Evaluation took place at baseline, post-treatment and one month after the end of treatment. Results showed that IMT and NIMT combined with SD significantly reduced craving in response to external drug-conditioned cues, while IMT appeared to be slightly more effective than NIMT in altering permissive thoughts on drug and alcohol use, depression symptoms and everyday life craving reactivity. Further investigation as to the role of music-assisted systematic desensitization as a therapeutic intervention for drug addiction treatment is warranted. / Grant from Grundtvig Education and Culture Lifelong Learning Program (agreement contract number 2013-1-FR1-GRU11-50690).

Introduction Allodynia is a type of neuropathic pain defined as pain due to a stimulus which does not normally provoke pain. There is little research and conflicting advice. The purpose of this thesis is to provide a summary of the current state of hand therapy knowledge. To accomplish this, a review of the hand therapy literature related to allodynia was conducted, along with the collection of expert opinion utilizing the Delphi survey technique. Methods International hand therapy experts were invited to participate in a classical Delphi study. Mixed methods were used to summarize each round and inform any subsequent questioning. Thematic analysis was used to look for patterns of meaning within the written responses. A consensus level of 75% was decided upon a priori for all final recommendations. Results Forty-three hand therapists from 15 countries contributed to the fourth and final round. Through the consensus process definitions related to allodynia, and assessments and treatments for allodynia, were explored and recommendations generated. Two themes were identified 1) assessment and treatment decisions depend on the client’s presumed underlying mechanisms contributing to the allodynia as well as psychosocial and functional status, and 2) whether the area of allodynia should be touched or not. Discussion and conclusions The literature and our survey results are mixed on whether it is beneficial to touch an area of allodynia. Other aspects related to allodynia such as functional or psychosocial impact are rarely addressed in the literature but were highlighted in our survey. This thesis contributes to the knowledge by presenting: 1) a summary of the current literature, 2) a new consensus definition of hypersensitivity, 3) experts’ recommendations for assessment and treatment of allodynia of the hand and factors to consider when utilizing these, and 4) recommendations for future research, practice, and education. / Thesis / Master of Science Rehabilitation Science (MSc) / Allodynia is when pain is caused by something that would normally not be painful such as a light touch or mild temperatures. It occurs when nerves become overly sensitive, and if this happens in the hand, it can limit how people use their hand and cause distress. There is little research to guide therapists and conflicting advice in textbooks on how to treat this. To help fill this gap, we conducted four online surveys with hand therapy experts. We found that expert therapists recommended assessments and treatments that look at how the person with allodynia is functioning and managing the pain. However, they disagreed on whether the painful area should be touched or not. This is important as it influences the advice given to clients and how treatment is delivered. More research is needed to compare approaches and to figure out what factors may influence how people with allodynia may respond to different treatments.

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Previous research shows that consuming violent media can lead to increased aggression in thoughts, feelings, and behaviors. Several other factors also contribute to such behaviors but have not been thoroughly studied including implicit beliefs about aggression in relation to media content. This two-part study consists of (1) an exploratory iterated principal-factor method to create an implicit belief measure about consuming violent media in conjunction with correlational analyses and (2) between subjects hierarchical linear regression models to determine what effects implicit beliefs have on subsequent aggression after participants view either a violent of nonviolent video, while controlling for violent media consumption and trait aggression, and accounting for desensitization. The first study successfully indicates which characteristics could be sued to define the implicit belief measure. The second study indicates that implicit beliefs about consuming violent media can affect aggressive outcomes moderated through desensitization and biological sex. The present study supports the assertion that implicit beliefs can affect aggressive outcomes but contradicts originally hypotheses.