Previous research has shown that cannabidiol (CBD), a non-psychoactive compound in the hemp plant Cannabis sativa, may be useful in treating drug craving, one of the hallmarks of drug addiction. However, the neural mechanism by which CBD attenuates craving is poorly understood. Studies from other laboratories have shown that neuroplastic changes associated with brain NMDA glutamate systems may at least partially serve as a neural mechanism for craving. In the current study, the noncompetitive NMDA receptor antagonist MK-801 maleate was used to induce locomotor sensitization, a form of NMDA glutamate-mediated neuroplasticity, in mice to test the sensitization-attenuating potential of CBD. Separate groups of mice (N=8) received either CBD (1.0 mg/kg, i.p.) or saline thirty minutes prior to an intraperitoneal injection of MK-801 (0.5 mg/kg, i.p.) or saline and tested for locomotor performance in an open field (Induction Trial). Seventy-two hours later all mice, regardless of drug pretreatment, were tested for locomotor activity following a second administration (0.5 mg/kg, i.p.) of MK-801 (Sensitization Trial). Results revealed a significant difference across groups for the Induction Trial, with groups receiving SAL-MK801 and CBD-MK801 significantly more active than SAL-SAL and CBD-SAL groups. Pretreatment with CBD had no effect on the locomotor activating effects of MK-801 during the Sensitization Trial with similar levels of locomotor performance across drug groups. Possibilities for the lack of CBD effects are discussed, as well as implications and future research directions.

No / Chronic pain is currently under-diagnosed and under-treated, partly because doctors' training in pain management is often inadequate. This situation looks certain to become worse with the rapidly increasing elderly population unless there is a wider adoption of best pain management practice. This paper reviews current knowledge of the development of chronic pain and the multidisciplinary team approach to pain therapy. The individual topics covered include nociceptive and neuropathic pain, peripheral sensitization, central sensitization, the definition and diagnosis of chronic pain, the biopsychosocial model of pain and the multidisciplinary approach to pain management. This last section includes an example of the implementation of a multidisciplinary approach in Belgium and describes the various benefits it offers; for example, the early multidimensional diagnosis of chronic pain and rapid initiation of evidence-based therapy based on an individual treatment plan. The patient also receives continuity of care, while pain relief is accompanied by improvements in physical functioning, quality of life and emotional stress. Other benefits include decreases in catastrophizing, self-reported patient disability, and depression. Improved training in pain management is clearly needed, starting with the undergraduate medical curriculum, and this review is intended to encourage further study by those who manage patients with chronic pain.

This study relates the sensitization process microstructural changes of 5083-H116 to its resulting corrosion resistance and mechanical performance. Alcoa 5083-H116 was sensitized in an environmental chamber at 100°C for up to ~1500 hours and 150°C up to ~2000 hours, revealing different degrees of sensitization based on exposure times. Microstructural characterization was conducted on etched sensitized samples. Additionally, samples were subjected to accelerated corrosion scenarios for subsequent microstructural examination and subsequent mechanical (tension and tensile creep) testing. To connect the laboratory studies to the field exposure, Novelis 5083-H116 was sensitized at 100°C; dog bone samples were created and exposed for two years in a beach environment to investigate possible sensitization and corrosion effects. It was found that the sensitization at 100°C and 150°C of Alcoa 5083-H116 led to recrystallization from the asreceived (AR) state of the material (3 mg/cm²). The degree of sensitization of 61 mg/cm² recrystallized the grain size the most from the AR state. The higher sensitization temperature of 150°C caused higher thickness loss and mass-loss rates (MR) for the intergranular corrosion (IGC) susceptible sensitization levels. Accelerated corrosion on different surface orientations led to different corrosion mechanisms (parallel IGC vs. perpendicular IGC). While 5083-H116 material corroded on the rolled surface led to a uniform exfoliation damage on 150°C sensitization exposure, the 100°C rolled surface only exhibited pitting corrosion damage. The through plate thickness corrosion damage, however, exhibited a corrosion susceptible-resistant-susceptible (CSRS) pattern. Mechanical properties were assessed for the various conditions in terms of room temperature tension testing and elevated temperature creep tests. Sensitization affected yield strength but did not play a role in ultimate tensile strength. The presence of corrosion damage lowered yield strength and ultimate tensile strength of the IGC susceptible sensitized 5083-H116, with the through thickness corrosion damage reducing the properties more than corrosion of the rolled surface. Material sensitized at 150°C and then corroded had a greater reduction in room temperature mechanical properties. Creep testing was performed at elevated temperatures, and it was found the solely sensitized 5083-H116 at 100°C or 150°C behaved the same as as-received 5083-H116. When corrosion damage was introduced, creep rupture times and secondary creep rates were changed. Once the corroded section area was accounted for, no significant difference in Larson-Miller parameters was observed. / Ph. D. / Aluminum is frequently replacing steel in the hulls of U.S. and Australians naval ships. It is preferred because of its lower density than steel and higher corrosion resistance which reduces the need to paint topside surfaces. However, when aluminum alloys that are used in ship construction are exposed to elevated temperatures, the corrosion resistance ca be considerably decreased. Furthermore, fire resistance is always a concern on naval ships. Accordingly, we are interested in predicting how aluminum ships that may have previously corroded respond to fires. In this study, a laboratory technique was used to speed up the corrosion process of these ship hull aluminum alloys. Some samples were thermally exposed in the laboratory for microscopic analysis, corrosion testing, and subsequent mechanical testing. To connect the laboratory studies to the field exposure, thermally exposed samples were placed on a beach for two years to investigate further environmental damages. It was found that the laboratory thermal exposure weakened the aluminum alloy. The thermally exposed alloys were weakened to the corrosion process. Different surfaces of the thermally exposed plates had different corrosion damage mechanisms. Mechanical properties were assessed for the various conditions in terms of room temperature tension testing and elevated temperature creep tests. Thermal exposure affected yield strength (the ability of the material to stretch) but did not play a role in ultimate tensile strength (maximum strength prior to breaking). The presence of corrosion damage lowered yield strength and ultimate tensile strength of the corrosion susceptible thermally exposed alloy. Creep testing (constant applied stress testing) was performed at elevated temperatures (representative of fire damage scenarios), and it was found that the solely thermally exposed alloy behaved the same as as-received alloy in terms of failure mechanisms. When corrosion damage was introduced, creep rupture times (time until material fails by breaking into two pieces) was reduced. Once the corrosion damage was accounted for, mechanical properties could be more accurately represented, and failure times (conditions in the alloy needs to be replaced on ships) were predicted for the alloy.

Master of Science / Department of Psychology / Mary E. Cain / Rats reared in an enriched condition (EC) with novel stimuli and social contact with cohorts display less sensitization to nicotine than rats reared under impoverished conditions (IC). However, it is currently unknown what effect differential rearing has on nicotine-induced conditioned hyperactivity. The present study determined whether differential rearing affects conditioning to a nicotine-associated context. In addition, this study also examined the effects of mecamylamine, an antagonist to nicotinic acetylcholine receptors, on conditioned hyperactivity and sensitization. This antagonistic drug has been shown to attenuate the locomotor effects of nicotine. In the current study, EC, IC, and social condition (SC) rats were reared from 21 to 51 days of age before training for the acquisition of conditioned hyperactivity and sensitization. Nicotine (0.4 mg/kg) was administered prior to 1-h locomotor sessions. Conditioned hyperactivity testing followed. Rats then received 5 sessions of sensitization training followed by a 16-day drug-free rest period before being tested for sensitization. Mecamylamine (1.0 mg/kg) was administered to rats prior to the conditioned hyperactivity test and sensitization test. Nicotine treatment resulted in sensitization and conditioned hyperactivity in all differential rearing groups. EC rats displayed less locomotor activity in response to nicotine than both IC and SC rats. Pretreatment with mecamylamine blocked the expression of conditioned hyperactivity in EC and SC rats and attenuated sensitization in all three rearing groups. These findings suggest that environmental enrichment may alter nAChR binding during development and may be a protective factor in the initiation and relapse of smoking behavior.

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.

As a major public health problem affecting more that 76.5 million Americans, chronic pain is one main reason why people seek medical attention. It is a pathological nervous system disorder that persists for months or years. Sensitization of nociceptive neurons in the dorsal horn of the spinal cord is crucial in the development of allodynia and hyperalgesia. The work presented in this thesis will focus on spinal protein kinase M zeta (PKMζ)-mediated plasticity and GABAergic disinhibition as spinal amplification mechanisms that orchestrate persistent changes in the dorsal horn of the spinal cord. As a result of central sensitization following peripheral nerve injruy, GABAergic disinhibition occurs due to an alteration in Cl- homeostasis via reduced KCC2 expression and function. Intrathecal administration of acetazolamide (ACT), a carbonic anhydrase inhibitor, attenuated neuropathic allodynia and spinal co-adminitation of ACT and midazolam (MZL), an allosteric modulator of the benzodiazepine class of GABAA receptors, synergistically inhibited neuropathic allodynia. Further studies concerning the impact of altered Cl-homeostasis via reduced KCC2-mediated Cl-extrusion capacity on the analgesic efficacy and potency of GABAA receptor agonist and allosteric modulators revealed that there is a differential regulation of the agonists and allosteric modulators at the GABAA receptor complex when Cl-homeostasis is altered. Another spinal amplification mechanism leading to central sensitization is PKMζ-mediated spinal LTP. In model of persistent nociceptive sensitization, allodynia induced by IL-6 injection or plantar incision was abolished by both the inhibition of protein translation machinery and PKMζ inhibitor, ZIP. However, only PKMζ inhibition prevented the enhanced pain hypersensitivity precipitated by a subsequent stimulus after the initial hypersensitivity had resolved, asserting that spinal PKMζ underlies the maintenance mechanisms of persistent nociceptive sensitization. Also, these results confirmed that the initiation mechanisms of persistent sensitization parallel LTP initiation mechanisms and the maintenance mechanisms of persistent sensitization parallel LTP maintenance mechanisms. Taken together, these results indicate that these amplification mechanisms drive a chronic persistent state in these models such that inhibition of these spinal amplication mechanisms will serve as an effective approach in the quenching chronic pain hypersensitivity in chronic pain models.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system that has high association with chronic pain syndromes such as fibromyalgia, migraine disorders, and chronic abdominal pain in adolescents with the diagnosis. Many of these disorders are characterized as central sensitization disorders, or pathological pain memory mediated by neural plasticity. Ehlers Danlos Syndrome Type 3 (EDS-3), also called joint hypermobility syndrome (JHS) is a genetic disorder of the connective tissue that causes joint laxity and is also highly associated with chronic pain syndromes as well as POTS. Methods: This study proposed to characterize POTS as a disorder of central sensitization. The hypothesis, presented within the proposed theoretical model, demonstrates that JHS leads to chronic pain that results in central sensitization and autonomic nervous system dysfunction (POTS). Other factors that were evaluated were anxiety and function. A sample size of 40 adolescents between the ages of 12 and 19 years were recruited from the cardiology and pain clinics at Children’s National Medical Center. Analysis of data utilizing Wilcoxon, Chi square, Pearson correlation, and logistic regression tests were completed using SAS 9.3. Results: In comparison to those without POTS, there were no significant associations found between having the diagnosis of POTS and any other variable studied in the model. JHS had a stronger correlation with anxiety, central sensitization, both subjectively, and objectively with hyperalgesia on Aδ sensory nerve fiber when compared to those without JHS. Subjective central sensitization was highly correlated with anxiety, function, age, and female gender. Function and central sensitization had a significant association even when removing anxiety as a covariate. Conclusions: These findings suggest that joint hypermobility may be a factor that contributes to the development of central sensitization in individuals with chronic pain. Dysautonomia is likely not a disorder of central sensitization, but rather a variable related to joint hypermobility and chronic pain in ways yet to be discovered. As previously discussed in other literature, anxiety has strong associations with central sensitization and functional disability in chronic pain syndromes, and when treated effectively may increase function in those that suffer with these disorders.

The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. While Radiation therapy is effective at killing tumor cells or inhibiting their growth initially, development of resistance to treatments and recurrence of tumors are major issues. One of the major goals of Dr. Gewirtz’s laboratory has been to develop strategies to overcome the resistance and attenuate disease recurrence. One of these attempts involve employing vitamin D and its analogs in combination with radiation therapy. Our proposed studies were based on a previous finding where vitamin D and vitamin D analogs such as EB 1089, were shown to enhance the response to radiation in breast cancer through the promotion of autophagy. We extended these studies to non-small cell lung cancer (NSCLC) and were able to validate that 1,25-D3 (the hormonally active form of vitamin D) and EB 1089 does in fact sensitize A549 and H460 cells and prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack the vitamin D receptor or functional p53, respectively, 1,25-D3 failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when p53 was induced in otherwise p53 null H1299 NSCLC cells. Sensitization by 1,25-D3/ EB 1089 was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D3 or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by the vitamin D receptor, p53 and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D3 and EB 1089 in NSCLC.

A sensibilização comportamental é caracterizada por aumento no efeito comportamental de uma droga após administrações repetidas. Este fenômeno é intensamente aplicado em estudos com modelos animais que enfocam a dependência de drogas. A maioria destas drogas promove adaptações em sistemas de neurotransmissão, (ex. sistema dopaminérgico), como é o caso da anfetamina, morfina e etanol. No entanto, estudos que avaliam os efeitos de drogas administradas durante a abstinência e posterior expressão de sensibilização comportamental são escassos. Neste trabalho avaliou-se as influências de um inibidor seletivo da monoamino-oxidase tipo-B (selegilina, 10mg/Kg) na sensibilização comportamental para anfetamina (2mg/Kg) observada em camundongos. Os resultados mostraram que o tratamento crônico com anfetamina promoveu sensibilização comportamental, efeito também observado no tratamento com selegilina, o qual resultou em sensibilização prévia para a anfetamina, além de potencializar os efeitos desta. Evidenciou-se também que a sensibilização comportamental não é um processo dependente dos níveis de corticosterona. O tratamento agudo com selegilina reduziu a atividade locomotora observada em campo aberto devido a hipotensão e bradicardia causadas pela mesma. Além disso, a selegilina agudamente também causou diminuição nos níveis de coticosterona motivo pelo qual é utilizada em clínica veterinária para o tratamento da Síndrome de Cushing. O tratamento agudo com anfetamina promoveu aumento no parâmetro comportamental, evidenciando seu efeito estimulante, mas não causou hipertensão. / The behavior sensitization is defined by a progressive enhancement of the behavioral response after repeated treatments. This phenomenon is intensely applied in studies with animal models that focus drug addiction. The majority of these drugs promote adaptations in neurotransmission (ex. dopaminergic system) as is the case of amphetamine, morphine and ethanol. However, studies which evaluate the drugs effects during abstinence and the induction of behavioral sensitization are scarce. In the present study we evaluated the influences of a selective inhibitor monoamine oxidase type-B (selegiline, 10mg/Kg) in the behavioral sensitization for amphetamine (2mg/Kg) in mice. The results shown that the chronic treatment with amphetamine promoted behavioral sensitization, like selegiline treatment that results in previous sensitization for amphetamine therefore potentiate the effects of this drug. Showed up that behavioral sensitization is not dependent process of the levels of corticosterone. The acute treatment with selegiline reduced the locomotor activity in open field test because of hypotension and decrease in heart rate. Another important acute effect of selegiline is the decrease in corticosterone levels; this is the cause that this drug is using in treatment of Cushing syndrome in veterinary. The acute treatment with amphetamine promoted increase in the locomotor activity, showing this stimulant effect but did not show effects in the blood pressure.

One of the most common childhood disorders, attention-deficit hyperactivity disorder (ADHD) places individuals at a higher risk for nicotine (NIC) dependence. Approximately 37.2% of individuals with ADHD currently smoke compared to the 18.3% of individuals with no record of mental illness. Methylphenidate (MPH; Trade name Ritalin) is the most commonly prescribed treatment for ADHD. Research regarding the synergistic effects of MPH and NIC, however, is divided. Some research indicates that MPH may enhance susceptibility to NIC effects, whereas other studies report that MPH may inhibit sensitization to NIC. The present study examines the effects of pre-exposure to MPH (1.0 mg/kg) on the behavioral effects of NIC (0.5 mg/kg) in adolescent male and female Sprague-Dawley rats. We used behavioral sensitization and conditioned place preference (CPP) on animals postnatal day (P)28-50; this is defined as adolescence in rats. For behavioral sensitization, results revealed a significant interaction between day of testing, drug pre-exposure, and adolescent drug treatment (p = .004). On the other hand, CPP results revealed a significant interaction between adolescent drug treatment and drug pre-exposure (p = .031). Findings suggest that pre-exposure to MPH reduces behavioral sensitization to NIC during adolescence. In addition, results indicate that MPH enhances NIC CPP in adolescent male and female rats, suggesting that MPH may enhance the rewarding effect of NIC.