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Abdominal pain places a large burden on society and its current management is sub-optimal due to the lack of visceral-specific analgesics. Voltage-gated sodium channels (Nav) are crucial for action potential generation and Nav1.9 has the lowest activation threshold of all these channels. In addition, Nav1.9 expresses a unique, slow, persistent current and is peripherally expressed on small diameter dorsal root ganglion (DRG) neurons. Whereas, at the level of the DRG, the Nav1.9 current is enhanced in response to a number of inflammatory mediators, no data exist for the role of Nav1.9 in signalling at the nerve terminal. Behavioural studies in mice have established a role for Nav1.9 in the response of somatic afferents to inflammatory mediators where it has a role in the immediate response of the afferents as well as in the development of hyperalgesia. No studies have investigated the role of Nav1.9 in the response of visceral afferents to inflammatory and mechanical stimuli. This thesis investigated the role of Nav1.9 in the response of visceral afferents to a variety of chemical and mechanical stimuli. Electrophysiological recording of colonic and intestinal afferents from Nav1.9 wild type and knockout mice were made using a bespoke recording chamber. The tissue was superfused with a number of chemical mediators and the change in peak afferent activity compared between wild type and knockout mice. For some experiments, human inflammatory supernatant was generated from inflamed and control appendices. The effect of this supernatant on visceral afferents and the role of Nav1.9 in this response were studied. The response of visceral afferents to intraluminal distension was also studied in Nav1.9 wild type and knockout mice. The data presented in this thesis demonstrate a pivotal role for Nav1.9 in the activation of visceral afferents by chemical and mechanical stimuli as well as a human inflammatory supernatant. The response of colonic and intestinal afferents to bradykinin, capsaicin and intraluminal distension is significantly attenuated in Nav1.9 knockout mice. Although the peak response of afferents to acetic acid was not significantly different between the genotypes, there were significant differences in the profile of the responses. Additionally, the data show that cyclooxygenase blockade enhances the effect of elimination of Nav1.9 on the response of afferents to noxious stimuli. Finally, the activation of visceral afferents by human inflammatory supernatants was significantly decreased in Nav1.9 knockout mice suggesting that blockade of this channel in man could provide analgesic effects that, due to its restricted peripheral distribution, would not be expected to be associated with the side effect profile of the current non-specific sodium channel blockers.

Made available in DSpace on 2014-06-11T19:31:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-26Bitstream added on 2014-06-13T21:02:11Z : No. of bitstreams: 1 lorena_sers_dr_botfmvz.pdf: 632999 bytes, checksum: 35174e377fd65ef6483f2f8509b96974 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O uso de analgésicos em animais é justificado moral e cientificamente. Para tal, é necessário que os profissionais saibam reconhecer e tratar a dor de forma adequada em animais. Objetivou-se correlacionar diversos dados demográficos para obter o perfil do médico veterinário brasileiro de grandes e pequenos animais. O questionário da pesquisa foi composto por: dados pessoais, utilização de fármacos analgésicos, analgesia, conduta no alívio da dor, uso de analgésicos em diversos procedimentos de grandes e pequenos animais, avaliação da dor e atualizações. A estatística foi realizada pelo programa SAS for Windows versão 9.1.3 com estatística descritiva com análise de frequência. Para as comparações simples foi utilizado o teste de qui-quadrado (x2). Foram obtidos 1.298 questionários de pequenos animais e 713 de grandes. Mulheres e profissionais graduados havia menos de dez anos conferiram maiores escores de dor que homens e profissionais formados havia mais de dez anos, porém a duração do tratamento não diferiu entre os gêneros. Os opioides mais utilizados para a analgesia foram tramadol (79%) e morfina (50,5%), em cães e gatos, e butorfanol (43,4%) e tramadol (39%) em grandes animais. Os efeitos adversos mais reportados dos opioides em gatos foram depressão respiratória e excitação. Em cães os principais efeitos adversos assinalados foram depressão respiratória e êmese. Para grandes animais, as preocupações com o uso desses fármacos foram: risco de excitação e síndrome cólica equina. Mais de 50% dos veterinários não utilizava opioides em bovinos. Os anti-inflamatórios não esteroidais (AINEs) mais escolhidos para pequenos animais foram meloxicam (81%) e cetoprofeno (70,4%), e flunixin meglumine (83,2%) e cetoprofeno (67,6%) em grandes animais. Os efeitos... / The use of analgesics in animals is morally and scientifically justified. According to that, the professionals should know how to recognize and treat pain in animals. The aim of this study was to correlate the demographic data of the Brazilian veterinarians, with the use of analgesics, the factors that affected the decision on the use of analgesia, attitudes, knowledge and methods of obtaining information on the evaluation and treatment of pain in animals. The questionnaire was composed of demographics, personal data, use of analgesics in general and specific procedures, analgesia, attitudes in the assessment and relief of pain and types of information in the area. The descriptive statistics with frequency analysis was performed using SAS for Windows 9.1.3. Chi-square (x2) for simple comparisons test was used. Questionnaires were obtained from 1298 small and 713 large animal veterinarians. Women and veterinarians graduated for less than ten years attributed higher pain scores than men, and veterinarians graduated for over ten years, but the frequency and duration of analgesic treatment did not differ between gender. The most commonly used opioid for analgesia of small animals were tramadol (79%) and morphine (50.5%) for dogs and cats, and butorphanol (43.4%) and tramadol (39%) for large animals. The most important side effects of opioids in small animals were respiratory depression and excitement, for cats and emesis in dogs and excitement and colic syndrome in 4 horses. NSAIDs of choice for small animals were meloxicam (81%) and ketoprofen (70.4%) and for large animals, flunixin meglumine (83.2%) and ketoprofen (67.6%). Side effects of NSAIDs most frequently reported for all species were gastric changes and nephrotoxicity. The most important limiting factors for the use of NSAIDs and opiods were the side effects for horses and the cost for cattles. The cats received lower pain... (Complete abstract click electronic access below)

Surgical embryo transfer in rodents is a common procedure in today’s research laboratory, although little is known of the effect analgesics may have on not only the recipient female but also the embryos. Two perioperative analgesics, ketoprofen and buprenorphine, were evaluated against a saline control in terms of number of pups born, number of pups weaned, and whether or not a litter was born. Both a uterine approach and an oviduct approach were evaluated. Post-surgical behavior was compared among the three surgical animals in each group, and between the non-surgical analgesic control and its surgical counterpart. Results indicated that ketoprofen and buprenorphine have no effect on the number of pups born, weaned, or litters born when compared to a saline control. Significant differences were found between the non-surgical analgesic control and its surgical counterpart in two behavioral categories; once for ketoprofen (behavior) and once for buprenorphine (physical condition). No other differences were found.

Thesis (D.M.S.)--Uppsala University, 2000. / "Acta Universitatis Upsaliensis." Extra abstract sheet inserted. Includes bibliographical references (p. 46-58).

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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.