This thesis is an investigation of the neurophysiologic mechanism, central sensitization, underlying pain and dysfunction in osteoarthritis. Central sensitization is an important mechanism in the pathophysiology of osteoarthritis but, to our knowledge, its influence on motoneurone excitability is unknown. Our primary hypothesis states that increasing central sensitization within a spinal segment will cause a greater increase in the excitability of motoneurones in subjects with osteoarthritis when compared to healthy controls. To test this hypothesis, we experimentally induced central sensitization in individuals and monitored the recruitment threshold force of the motor units in the first dorsal interosseous muscle using indwelling electromyography. Findings from this study suggest that central sensitization lowers the motor unit recruitment threshold in osteoarthritis compared to healthy individuals. Motoneurone excitability might be inhibited in healthy individuals with persistent sensitization as well. Thus, central sensitization is an important consideration in the biomechanical dysfunction seen in osteoarthritis. / Canadian Arthritis Network

Repeated administration of psychostimulant drugs induces a long-term state of sensitization in the mesolimbic dopamine system. This hyperdopaminergic state is associated with enhanced reward-seeking behaviors. Such aberration of incentive motivational processing is suggested to facilitate the initiation and maintenance of compulsive drug-taking behaviors. A defining characteristic of addiction is the persistence to pursue drug reinforcement despite negative consequences associated with administration. Thus, it is likely that addicts frequently experience states of motivational conflict to both seek and avoid the drug. The present study investigated the effects of repeated cocaine exposure on goal-seeking behaviors in rats, utilizing conflict paradigms wherein positive and negative incentive motivations were simultaneously evoked. Here it was shown that cocaine-experienced rats displayed both enhanced approach and avoidance behaviors, depending upon the conditions put forth in each paradigm. The results contribute to elucidating the consequences of drug administration upon basic motivational processes that may influence compulsive drug-taking behaviors.

The behavioral effects of drugs that act on the brain’s dopamine (DA) system change with repeated exposure to the drug. Antipsychotic drugs, that block DA receptors, produce progressively greater effects on behavior with repeated testing. For example, rats repeatedly treated with a low dose of the D2 receptor-preferring antagonist haloperidol do not initially exhibit catalepsy, a response quantified by time spent on a horizontal bar without active movement. However, with repeated drug-environment pairings animals show a reduction in exploration and increases in catalepsy. The current thesis examined the drug-environment relationship in catalepsy sensitization, and how different DA receptor subtypes control this phenomenon. Treatment with a D2, but not D3 or D1-like receptor-preferring antagonist produced catalepsy sensitization. Catalepsy sensitization developed in one test environment did not transfer to another environment. Similarly, rats with a history of haloperidol treatments outside of the test environment (unpaired group) did not exhibit significant catalepsy when given haloperidol for the first time prior to catalepsy testing. Previous exposure to the catalepsy test environment led to a more rapid development of catalepsy sensitization. Thus, drug-environment interaction is critical for the development and expression of catalepsy sensitization. Rats previously given haloperidol and tested with saline in the drug paired environment exhibited conditioned catalepsy. The acquisition of conditioned catalepsy is dependent on D1-like receptors, while its expression is dependent on D3 receptors. Conditioned catalepsy showed gradual day-to-day extinction with repeated saline treatment in the previously haloperidol-paired environment. Following extinction, the response to haloperidol in previously sensitized rats shifted from environment-specific to environment-independent suggesting that a putative haloperidol drug cue alone can elicit conditioned catalepsy. In summary, treatment with a D2, but not D1-like or D3 receptor-preferring antagonist in a particular test environment produces catalepsy sensitization, while acquisition of conditioned catalepsy is dependent on D1-like receptors, and its expression is dependent on D3 receptors. Importantly, the acquisition and expression of sensitization to haloperidol is conditional on the presence of drug-associated environmental stimuli. Our findings provide further insight into the current understanding of learning processes involved in the action of antipsychotic drugs and the dissociable effects of D1-like, D2 and D3 receptors controlling this phenomenon. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-08-12 15:51:00.467

Functional magnetic resonance imaging (fMRI) studies performed to date have focused on brain structures rostral to the thalamus, although the first level of sensory information and pain transmission occurs at the spinal cord (SC). The primary goal of this project is to map activity using fMRI, from the entire cervical SC and brainstem following innocuous and noxious stimuli before and after peripheral sensitization in normal human volunteers. This study is unique in that it determines functional activity throughout the lower neural axis in response to mechanical stimuli that are perceived as painful only after sensitization. Functional MRI studies of the SC were carried out in 18 healthy individuals in a 3T Siemens Magnetom Trio. Innocuous touch and brush (n=8), and noxious touch (n=10) stimuli were applied before and after peripheral sensitization. Peripheral sensitization was induced by topical application of capsaicin. Functional image data spanned from the C7/T1 disc to the superior edge of the thalamus and analyzed using a general linear model to discriminate signal intensity changes from physiological motion. Normalized results were combined to demonstrate the number of volunteers showing activity at each location on a voxel-by-voxel basis. Areas of activity were superimposed onto anatomical transverse drawings and identified visually with comparison to several stereotaxic atlases. The results from this study confirm previous reports that a non-noxious stimulus translates into a pain response after peripheral sensitization. The brush stimulus, before sensitization activated areas in the ipsilateral dorsal horn (DH), gracile and cuneate nuclei in the medulla and areas surrounding the dorsal column medial lemniscal pathway. Peripheral sensitization produced activity in the contralateral ventral horn (VH), typical of a pain response. The innocuous von Frey stimulus produced activity in typical sensory centres in the DH and brainstem before sensitization, and areas more consistent with a noxious response after sensitization. When examining equi-nociceptive stimuli in a control versus sensitized state, the noxious touch stimuli showed similar activation patterns even though the force of the filaments were different. In all experiments there was indication of descending modulation as activity was observed in the periaqueductal gray, midbrain red nuclei and pontine reticular formation. This study demonstrates how non-painful and pain information is transmitted from the dorsal spinal horn to the brain in healthy individuals and how peripheral sensitization induces changes in non-noxious stimuli that correlate with pain sensory transmission. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2008-09-24 20:13:08.655

Repeated administration of psychostimulant drugs induces a long-term state of sensitization in the mesolimbic dopamine system. This hyperdopaminergic state is associated with enhanced reward-seeking behaviors. Such aberration of incentive motivational processing is suggested to facilitate the initiation and maintenance of compulsive drug-taking behaviors. A defining characteristic of addiction is the persistence to pursue drug reinforcement despite negative consequences associated with administration. Thus, it is likely that addicts frequently experience states of motivational conflict to both seek and avoid the drug. The present study investigated the effects of repeated cocaine exposure on goal-seeking behaviors in rats, utilizing conflict paradigms wherein positive and negative incentive motivations were simultaneously evoked. Here it was shown that cocaine-experienced rats displayed both enhanced approach and avoidance behaviors, depending upon the conditions put forth in each paradigm. The results contribute to elucidating the consequences of drug administration upon basic motivational processes that may influence compulsive drug-taking behaviors.

No description available.

When a human or animal is threatened or confronted with a stimuli signalling danger, internal defence mechanisms are activated that evoke feelings of fear and anxiety. These emotional responses promote the behaviour patterns necessary for an organism's survival. Animal research seeks to understand how these emotions affect behaviour both physiologically and neurologically in order to develop effective treatment for those suffering from severe anxiety disorders. The aim of this thesis was to examine the role of the amygdala, and dorsal and ventral hippocampus in relation to immediate fear arousal brought on by footshock. This was assessed by examining whether muscimol would interfere with the acoustic startle response before or after footshock presentation, and then comparing these reactions to a control group that received saline infusions. The results of this research are extremely important because they identify various brain structures involved in the fear-arousing effects of footshock as measured by the shock sensitization of acoustic startle. Laboratory rats received muscimol (0.1ug and 0.01ug) infusions into the basolateral amygdala, dorsal and ventral hippocampus. These three brain regions have been identified as playing a prominent role in fear neurocircuitry. The results demonstrated that the GABA A receptor agonist muscimol in doses of 0.1ug and 0.01ug reliably blocked shock sensitization of the acoustic startle response. The muscimol doses did not alter the shock reactivity amplitudes therefore indicating a normal perception of the fear arousing properties of footshock. Therefore, the present study's results suggest that a decrease of GABA activity in the amygdala, dorsal and ventral hippocampus may be essential for the neuronal basis of fear acquisition and expression of unconditioned and conditioned stimuli.

OBJECTIVES: This study aims to explore the relationships between preoperative psychosocial factors in relation to postoperative chronic pelvic pain (CPP) in adolescents and young women with endometriosis, which is a significant public health concern. As a pilot sample, there is large need to present preliminary data exploring the biopsychosocial correlates and possible predictors of central sensitization and CPP, which remains non-existent in the realm of adolescents and young adults with CPP secondary to endometriosis. METHODS: Eligible candidates included patients 12-22 years old who were diagnosed with CPP after laparoscopic confirmation of endometriosis. 25 successfully enrolled subjects had pre-surgical information obtained from baseline surveys and underwent a postoperative sensory protocol to assess mechanical allodynia, pressure pain sensitivity, central sensitization, and a self-report measure of pain sensitivity. Correlation calculations were conducted between pre-surgical factors (pain intensity, pain catastrophizing (PCS), and quality-of-life (from SF-36)) and post-surgical factors (pain and sensitivity thresholds as measured by QST and the PSQ) in the subject population as a whole, and in two population subgroups: those exhibiting central sensitization and those who are not. One-way ANOVA calculations and one sample t-tests were conducted to compare differences between cohorts and between abdominal and control sites for various study parameters. RESULTS: 6 of 25 (24%) subjects experienced a wind-up phenomenon during the temporal summation for pain test, serving as a surrogate for central sensitization. The differences in study parameters that this group (+CS) exhibited in comparison to the –CS group, failed to reach significance in all study parameters. Both cohorts exhibited positive correlations between pre-operative disability due to bodily pain (SF-36) and sensitivity of the abdomen, as well as negative correlations between disability due to bodily pain and pressure pain thresholds of the abdomen. The +CS cohort also exhibited a negative correlation between disability due to bodily pain and pinprick pain scores, a positive correlation between role limitations due to physical health (SF-36) and sensitivity of the abdomen, and a positive correlation between pain catastrophizing and sensitivity of the abdomen. As a whole, the subject population had significantly higher levels of catastrophizing than published means. In all cohorts, pressure pain thresholds of the abdomen were significantly lower than the control values, and PSQ-minor scores were significantly higher than published means. CONCLUSIONS: Results suggest the importance of pre-operative pain and psychosocial functioning on pain outcomes, particularly when considering subjects presenting with central sensitization, in young women with CPP secondary to endometriosis. The results indicate the need for a larger sample as well as established control values to further explore the relationships between these variables.

OBJECTIVES: This study aims to better understand the relationship between psychosocial factors and the development of chronic pelvic pain (CPP) in cases of adolescent endometriosis, specifically mood disorders, pain catastrophizing and quality of life, and to detect the development of central sensitization within this population. METHODS: Eligible candidates were patients between 14 and 22 years old with confirmed diagnosis of endometriosis and chronic pelvic pain who were enrolled in the Women’s Health Study: From Adolescence to Adulthood through the Boston Center for Endometriosis (BCE) and Boston Children’s Hospital. The administration of quantitative sensory testing (QST) to assess mechanical touch perception, pressure pain sensitivity and temporal summation was performed on 48 subjects. Pre-surgical baseline surveys, which included pain catastrophizing and quality of life measures, were obtained from the BCE. Record of diagnosed mood disorder (anxiety/depression) was obtained through medical chart review. Pearson correlations between QST measures, pain catastrophizing, presence of mood disorders or central sensitization and pre-surgical pain scores were conducted. One-way ANOVA calculations, and one sample and paired t-tests were conducted to gain further understanding of these variables as they relate to groups within the cohort. RESULTS: Regarding QST measures, 23 subjects (47.9%) produced a wind-up phenomenon from temporal summation during QST administration, which serves as a surrogate for the presence of central sensitization (+CS). Pressure sensation and pain scores correlated at all test sites (lower and upper abdomen, as well as finger control site) and wind-up phenomenon correlated in the lower and upper abdomen throughout the cohort. For the presence of mood disorders, anxiety and depression were equally distributed across the +CS and –CS groups. Review of pre-surgical pain scores and pain catastrophizing (PCS) within the cohort had significant correlations between pre-surgical pain and PCS subsets of rumination and magnification. PCS total and subset scores also correlated to +CS. One-way ANOVA calculations showed the cohort as a whole presented with clinically significant helplessness. CONCLUSIONS: Results encourage further investigation of the relationship between endometriosis, comorbid conditions, environmental factors and the development of CPP within the adolescent population. More detailed data regarding mental health and documentation of condition progression, as well as establishment of health control values and sample growth are encouraged for the continued progress of this project. / 2020-07-03T00:00:00Z

Patients with subacromial pain syndrome (SPS) display a number of sensorimotor deficits including alterations in pain processing, poor proprioception, and weakness at the symptomatic limb. The primary purpose of this dissertation was to explore whether the aforementioned deficits: (1) can be quantified by using the non-involved limb as a measure of control, (2) are purely localized to the symptomatic limb or represent a more generalized deficit, (3) are influenced by the presence of subacromial pain, and (4) present similarly in male and female patients. Here, we utilized modern clinical techniques in both a patient cohort with SPS and uninjured control cohort to address these aims. The results of this dissertation are applicable towards treatment of SPS as well as scientific understanding of sex on sensorimotor behavior.