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Pain management options for the equine orthopedic patient are limited and can have harmful systemic effects. Methods of local drug delivery such as intravenous regional limb perfusion (IVRLP) are able to provide more focal therapy with a decreased risk of systemic side effects. The primary goal of the present study was to develop a novel, targeted pain management approach able to mitigate the complications encountered with systemic opioid administration. There were two main objectives with respect to elucidating the usefulness of a butorphanol IVRLP. The first of these was to evaluate the feasibility of IVRLP to deliver butorphanol to the treated limb, and the second was to develop a method for evaluating the analgesic efficacy of the procedure. The findings suggest butorphanol IVRLP is well tolerated, results in measurable levels of butorphanol in the treated limb and may be of analgesic benefit.

The murine model has been used to investigate the role of cardiac sensory axons in various disease states. However, the distribution and morphological structures of cardiac nociceptive axons in normal murine tissues have not yet been well characterized. In this study, whole-mount atria from FVB mice were processed with calcitonin gene-related peptide (CGRP) and substance P (SP) primary antibodies followed by secondary antibodies, and then examined using confocal microscopy. We found: 1) Large CGRP-IR axon bundles entered the atria with the major veins, and these large bundles bifurcated into small bundles and single axons that formed terminal end-nets and free endings in the epicardium. Varicose CGRP-IR axons had close contacts with muscle fibers, and some CGRP-IR axons formed varicosities around principle neurons (PNs) within intrinsic cardiac ganglia (ICGs). 2) SP-IR axons also were found in the same regions of the atria, attached to veins, and within cardiac ganglia. Similar to CGRP-IR axons, these SP-IR axons formed terminal end-nets and free endings in the atrial epicardium and myocardium. Within ICGs, SP-IR axons formed varicose endings around PNs. However, SP-IR nerve fibers were less abundant than CGRP-IR fibers in the atria. 3) None of the PNs were CGRP-IR or SP-IR. 4) CGRP-IR and SP-IR often colocalized in terminal varicosities around PNs. Collectively, our data document the distribution pattern and morphology of CGRP-IR and SP-IR axons and terminals in different regions of the atria. This knowledge provides useful information for CGRP-IR and SP-IR axons that can be referred to in future studies of pathological remodeling.

The objective of this study was to evaluate effects of extracorporeal shockwave therapy (ESWT) on spinal mechanical nociceptive threshold (MNT) and multifidus muscle cross-sectional area (CSA) in horses with thoracolumbar pain. We hypothesized that ESWT would increase MNT and multifidus CSA. Twelve horses with thoracolumbar pain were included. Prior to treatment, each thoracolumbar spine was radiographed to document existing pathology. Horses received 3 ESWT treatments, 2 weeks apart (days 0, 14, 28). Palpation scores were documented (days 0, 45, 65) and ultrasonographic CSA of left and right multifidus was recorded at T12, T14, T16, T18, L3 and L5 (days 0, 45, 65). MNT was measured at T12, T14, T16, T18, L3 and L5 every 7 days (day 0-56). Change in MNT in 10/12 horses was significant at each timepoint compared to day 0 (P<0.05). MNT increased at all timepoints at 6 sites in 2/12, at 5 sites in 3/12, at 4 sites in 4/12 and at 1 site in 1/12 (P<0.05). MNT average percent increase from day 0-56 was 64% for T12-T18 and 29% for L3-L5. There was no statistical difference in MNT from day 35-56 (P=0.25). A bimodal analgesic trend was observed following ESWT. Degree of radiographic change was not associated with response to treatment and no significant change in multifidus CSA was observed. In conclusion, 3 treatments of ESWT 2 weeks apart raised MNT over a 56-day period in horses with back pain, but did not influence change in CSA of the multifidus. / Master of Science / Back pain in the horse is a frequently diagnosed and treated cause of back stiffness, lameness, poor performance and/or avoidance behavior under saddle. Treatment is focused on reducing pain and inflammation and on strengthening and promoting proper muscle development to maintain long term results. Recently, rehabilitation of the deep spinal stabilizer multifidus muscle, particularly with regard to increased cross-sectional area (CSA), has become a focus of targeted physiotherapy. Assessment of the degree of pain is subjective due to individual interpretation and palpation technique. In an attempt to standardize quantification of pain, pressure algometry has become a validated, objective and repeatable measure of axial skeleton mechanical nociceptive threshold (MNT), which is defined as the minimum pressure required to induce a pain response. Although many treatment options for back pain exist, there is limited research documenting the efficacy of these treatments in horses. Extracorporeal shockwave therapy (ESWT), which consists of focused, high velocity acoustic waves, is one type of non-invasive, well-tolerated treatment for back pain. Despite its popularity, there is no research documenting the effects of ESWT on equine spinal MNT or multifidus muscle CSA. This is the first study to document the effects of ESWT on spinal MNT and multifidus muscle CSA in horses with back pain. We hope that the results of this study will help guide treatment decisions for horses with back pain.

The electroencephalogram (EEG) reflects summated, slow post-synaptic potentials of cortical neurons. Sensory, motor or cognitive events (such as a fast-rising sensory stimulus, a brisk self-paced movement or a stimulus-triggered cognitive task) can elicit transient changes in the ongoing human EEG, called event-related potentials (ERPs). ERPs are widely used in clinical practice, and believed to reflect the activity of the sensory system activated by the stimulus (for example, laser-evoked potentials are used to substantiate the neuropathic nature of clinical pain conditions). When ERPs are elicited by pairs or trains of stimuli delivered at short inter-stimulus intervals (ISIs), the magnitude of the ERP elicited by the repeated stimuli is markedly reduced, a phenomenon known as response decrement. While the interval between two consecutive stimuli becomes longer, the reduced response is recovered. Thus, this phenomenon has been traditionally interpreted in terms of neural refractoriness of generators of ERPs ("neural refractoriness hypothesis"). This thesis, however, challenges this neural refractoriness hypothesis by describing the results of manipulating the preceding events of the eliciting stimulus. The first study examined the effect of variable and short ISIs on sensory ERPs, delivering trains of auditory and electrical stimuli with random ISIs ranging from 100 to 1000ms. In the second study, pairs of laser stimuli were presented in two comparable conditions. In the constant condition, the ISI was identical across trials in each block, while in the variable condition, the ISI was variable across trials. By directly comparing ERPs elicited by laser stimulation, this study aimed to explore whether lack of saliency in the eliciting stimulus could explain the response decrement during stimulus repetition. Finally, the third study tested the hypothesis that the reduced eliciting ERPs would recover if saliency were introduced by changing the modality of the preceding event. Thus, trains of three stimuli (S1-S2-S3) with 1s ISI were presented; S2 was either same or different in modality as S1 and S3 in each block. Results from these three experiments demonstrate that this "refractoriness hypothesis" does not hold, and suggest that the magnitude of ERPs is only partly related to the magnitude of the incoming sensory input, and instead largely reflects neural activities triggered by salient events in the sensory environment. These results are important for the correct interpretation of ERPs in both physiological and clinical studies.

Dor em pediatria tem sido o foco de muitos estudos nas últimas décadas devido ao fato de que neonatos apresentam menor limiar a estímulos nocivos e inócuos em relação aos adultos. Desta forma, o uso de analgésicos é frequente para sedação e analgesia em UTIs pediátricas, e entre os opioides, a morfina é um dos mais utilizados. Adicionalmente, exposição a estímulos estressantes como a deprivação materna está entre os fatores ambientais relacionados a alterações no desenvolvimento neural. O estresse social ou a negligência do cuidado parental, e mais precisamente do cuidado materno em ratos, está associado a importantes alterações comportamentais na vida adulta. Entre estas alterações apresentadas ao longo da vida estão alterações na resposta ao estresse, e à alteração na sensibilidade a estímulos dolorosos, indexadas por hiperalgesia. Consquentemente, o estresse social gerado pela deprivação materna está relacionado a prejuízos cognitivos, emocionais e sociais, além de alterações neuroquímicas de longo prazo. Deste modo, é necessário atenção, prevenção e tratamento a esses eventos físicos, emocionais e comportamentais no período neonatal e durante a infância, uma vez que as bases neurobiológicas envolvidas nestes fenômenos ainda não foram completamente elucidadas. Considerando a relevância do tema, o objetivo deste estudo foi verificar os efeitos do tratamento com 5 μg de morfina, uma vez ao dia, do P8 ao P14 e a exposição a deprivação materna por 3 horas durante os primeiros 10 dias de vida em curto (P16), médio (P30) e longo prazo (P60), sobre o desenvolvimento dos reflexos neuromotores da prole por meio do Reflexo de Endireitamento, Geotaxia Negativa e Marcha; comportamento nociceptivo por meio dos testes Tail-Flick e Placa Quente, respectivamente. Um total de 58 filhotes foi utilizado. Os animais foram divididos em 5 grupos: controle total (C), que não recebeu nenhuma intervenção; salina (S), que recebeu solução salina; morfina (M), que recebeu morfina; deprivado salina (DS), que foram submetidos a deprivação maternal e receberam solução salina; e deprivado morfina (DM), que foram submetidos a deprivação maternal e receberam morfina. Em relação aos testes neuroquímicos, foram analisados níveis de BDNF, NGF, IL-1β e IL-4 em tronco e córtex cerebral que estão relacionados a fenômenos modulatórios em sistemas nervoso e imune. Os animais que receberam morfina e os deprivados maternos que receberam morfina apresentaram atraso no desenvolvimento dos reflexos iniciais. Alterações neuroquímicas também foram observadas. Os níveis de BDNF no tronco encefálico foram diminuídos em animais que receberam morfina e deprivação materna. Animais deprivados apresentaram um aumento nos níveis de NGF no tronco encefálico. Além disso, observou-se um aumento nos níveis de NGF do córtex cerebral em animais que receberam morfina, deprivados maternos e deprivados maternos que receberam morfina. Uma diminuição no limiar nociceptivo foi observada em animais que receberam morfina, deprivados maternos e os deprivados maternos que receberam morfina. Também houve interações em tronco encefálico e córtex cerebral nos níveis de BDNF, IL-1β e IL-4 entre as variáveis independentes: tratamento, deprivação e tempo, o que levou à modificação nos níveis centrais dos neuroimunomoduladores avaliados. Estes dados demonstram a importância de estudos focados nos efeitos do tratamento com morfina no período neonatal ao longo da vida, assim como na busca por alternativas terapêuticas que possam reverter possíveis alterações decorrentes da separação materna no período neonatal. / Pediatric pain has been the focus of many studies in the last decades due to the fact that neonates have a lower threshold for innocuous and noxious stimuli than for adults. Thus, the use of analgesics is frequent for sedation and analgesia in pediatric intensive care units, and among opioids, morphine is one of the most used. Additionally, exposure to stressful stimuli such as maternal deprivation is among the environmental factors related to changes in neural development. The social stress or neglect of parental care, and more precisely maternal care in rats, is associated with important behavioral changes in adult life. Among these changes presented throughout life are changes in the response to stress, and the change in sensitivity to painful stimuli, indexed by hyperalgesia. Consequently, the social stress generated by maternal deprivation is related to cognitive, emotional and social impairments, further to long-term neurochemical changes. Thus, attention, prevention and treatment are necessary to these physical, emotional and behavioral events in the neonatal period and during childhood, since the neurobiological bases involved in these phenomena have not yet been fully elucidated. Considering the relevance of the subject, the objective of this study was to verify the effects of treatment with 5 μg of morphine once a day from P8 to P14 and exposure to maternal deprivation for 3 hours during the first 10 days of short (P16), medium (P30) and long- term (P60), on the development of neuromotor reflexes of offspring through the righting Reflex, Negative Geotaxis and Gait; nociceptive behavior through the Tail-Flick and Hot Plate tests, respectively. A total of 58 puppies were utilized. The animals were divided in 5 groups: the total control group (C), which did not receive any intervention; saline group (S), which receive saline solution; morphine group (M), which receive morphine; deprived saline (DS), which were subjected to maternal deprivation and receive saline solution; and deprived morphine group (DM), which were subjected to maternal deprivation and receive morphine. In relation to the neurochemical tests, levels of BDNF, NGF, IL-1β and IL-4 were analyzed in the brainsteam and cerebral cortex and are related to modulatory phenomena of the nervous and immune systems. Animals that received morphine and deprived animais that received morphine showed a delay in the development of early reflexes. Neurochemical changes were also observed. BDNF levels in the brainstem were decreased in animals receiving morphine and maternal deprivation. Deprived animals had an increase in NGF levels in the brainstem. Besides, an increase in NGF levels of the cerebral cortex was observed in animals receiving morphine, maternal deprivation and maternal deprivation receiving morphine. A decrease in the nociceptive threshold was observed in animals receiving morphine, maternal deprivation, and maternal deprivation receiving morphine. There were also interactions in the brainstem and cerebral cortex in the levels of BDNF, IL-1β and IL-4 among the independent variables: treatment, deprivation and time, which led to the modification in the central levels of the neuroimmunomodulators evaluated. These data demonstrate the importance of studies focused on the effects of treatment with morphine in the neonatal period throughout life, as well as on the search for therapeutic alternatives that may reverse possible changes due to maternal deprivation in the neonatal period.