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Antagonism by Haloperidol and Its Metabolites of Mechanical UNIVERSIDAD DE GRANADA FACULTAD DE MEDICINA INSTITUTO DE NEUROCIENCIAS Y DEPARTAMENTO DE FARMACOLOGÍA ROLE OF SIGMA-1 RECEPTORS IN CAPSAICIN-INDUCED MECHANICAL HYPERSENSITIVITY: STUDIES WITH SIGMA-1 LIGANDS, KNOCKOUT MICE AND ANTISENSE OLIGODEOXYNUCLEOTIDES TESIS DOCTORAL PRESENTADA POR José Manuel Entrena Fernández, Licenciado en Bioquímica, para optar al grado de: DOCTOR POR LA UNIVERSIDAD DE GRANADA Habiendo obtenido la Suficiencia Investigadora dentro del Programa de Doctorado “Neurociencias” en el Área de Conocimiento de Farmacología Granada, 2009 Editor: Editorial de la Universidad de Granada Autor: José Manuel Entrena Fernández D.L.: GR. 2059-2009 ISBN: 978-84-692-2259-1 Instituto de Neurociencias “F. Oloriz” Universidad de Granada D. JOSÉ MANUEL BAEYENS CABRERA, CATEDRÁTICO DEL DEPARTAMENTO DE FARMACOLOGÍA E INVESTIGADOR DEL INSTITUTO DE NEUROCIENCIAS DE LA UNIVERSIDAD DE GRANADA CERTIFICA: Que el trabajo de investigación titulado “ROLE OF SIGMA-1 RECEPTORS IN CAPSAICIN-INDUCED MECHANICAL HYPERSENSITIVITY: STUDIES WITH SIGMA-1 LIGANDS, KNOCKOUT MICE AND ANTISENSE OLIGODEOXYNUCLEOTIDES” ha sido realizado por D. José Manuel Entrena Fernández, para optar al grado de Doctor por la Universidad de Granada, en el Instituto de Neurociencias y el Departamento de Farmacología de la Facultad de Medicina de la Universidad de Granada, bajo mi dirección. Y para que conste donde proceda se firma este certificado en Granada a 27 de Febrero de 2009 Fdo. José Manuel Baeyens Cabrera Fdo. José Manuel Entrena Fernández Facultad de Medicina. Avda. de Madrid, 11- 18012 Granada Tel.: 958 244 033. Fax: 958 246 187. E-mail:[email protected] DÑA. ESPERANZA DEL POZO GAVILÁN, PROFESORA TITULAR DEL DEPARTAMENTO DE FARMACOLOGÍA E INVESTIGADORA DEL INSTITUTO DE NEUROCIENCIAS UNIVERSIDAD DE GRANADA CERTIFICA: Que el trabajo de investigación titulado “ROLE OF SIGMA-1 RECEPTORS IN CAPSAICIN-INDUCED MECHANICAL HYPERSENSITIVITY: STUDIES WITH SIGMA-1 LIGANDS, KNOCKOUT MICE AND ANTISENSE OLIGODEOXYNUCLEOTIDES” ha sido realizado por D. José Manuel Entrena Fernández, para optar al grado de Doctor por la Universidad de Granada, en el Instituto de Neurociencias y el Departamento de Farmacología Universidad de Granada, bajo mi dirección. Y para que conste donde proceda se firma este certificado en Granada a 27 de Febrero de 2009 Fdo. Esperanza del Pozo Gavilán Fdo. José Manuel Entrena Fernández D. ENRIQUE JOSÉ COBOS DEL MORAL, INVESTIGADOR DEL DEPARTAMENTO DE FARMACOLOGÍA Y SUPERVISOR DE LA INSTALACIÓN RADIACTIVA DEL CENTRO DE INVESTIGACIONES BIOMÉDICAS DE LA UNIVERSIDAD DE GRANADA. CERTIFICA: Que el trabajo de investigación titulado “ROLE OF SIGMA-1 RECEPTORS IN CAPSAICIN-INDUCED MECHANICAL HYPERSENSITIVITY: STUDIES WITH SIGMA-1 LIGANDS, KNOCKOUT MICE AND ANTISENSE OLIGODEOXYNUCLEOTIDES” ha sido realizado por D. José Manuel Entrena Fernández, para optar al grado de Doctor por la Universidad de Granada, en el Instituto de Neurociencias y el Departamento de Farmacología Universidad de Granada, bajo mi dirección. Y para que conste donde proceda se firma este certificado en Granada a 27 de Febrero de 2009 Fdo. Enrique José Cobos del Moral Fdo. José Manuel Entrena Fernández La realización de esta tesis ha sido posible gracias a una beca predoctoral del Ministerio de Educación y Ciencia y a la financiación de nuestro grupo de investigación por la Junta de Andalucía (grupo CTS-109), por el CDTI (proyecto CENIT Genius Pharma), Ministerio de Educación y ciencia (proyecto SAF 2006-06122) y por Laboratorios Dr. Esteve S.A. A mis padres, por darme la oportunidad que ellos nunca tuvieron Agradecimientos Quiero expresar mi gratitud a todas las personas que con su apoyo y consejo me han ayudado durante todos estos años, tanto en el laboratorio como fuera de él. A Jose y Esperanza. Se me quedan cortas las palabras. Ya que desde aquel 21 de Abril de 2003 que me brindasteis la oportunidad de formarme como investigador aceptándome en vuestro grupo de investigación, me he sentido como en casa, sintiéndome un miembro útil y valorado, tanto científica como personalmente desde el primer día. Creo sinceramente que ambos sois modelos a seguir, no sólo por vuestra calidad científica, sino también por vuestra calidad humana. Después de estos años no sólo habéis sido mis Directores de Tesis, además habéis demostrado continuamente ser mis amigos. A Jose. Me siento un afortunado de haber tenido un Director de Tesis como tú, ya que la confianza y dedicación diaria que has derrochado durante estos años conmigo han sido ejemplares para mí, tanto en lo científico como en lo personal. Gracias por todo lo que he aprendido de ti durante estos años, no sólo como investigador, sino también como persona. Estoy muy orgulloso de haber realizado esta Tesis bajo tu dirección. A Esperanza. Por tu positivismo, consejos y disponibilidad en cualquier momento, que han sido de gran ayuda cuando me surgía cualquier problemilla (que no han sido pocos). Eres una Directora de Tesis excepcional, no sólo por tus valores científicos, sino también por tu amabilidad. Eres un ejemplo a seguir tanto en el laboratorio como fuera de él. A Kike. Un excelente compañero y mejor persona, que durante todos estos años y especialmente en la última fase de mi Tesis ha sido un apoyo incondicional. Estoy muy orgulloso que seas uno de mis Directores de Tesis. Os deseo lo mejor a ti y a Teresa (su esposa) en vuestra nueva aventura. Gracias tío por todo. A mis compañeros a la par que amigos del Departamento: Cruzmi (Chusmi), José Miguel (Pujolete), Paco (El grande), Luís y a las dos nuevas incorporaciones Cristina y Rafa. Que decir de ellos…, siempre hemos ido todos a una, apoyándonos en todo lo que hacemos y compartiendo nuestras inquietudes. Hemos trabajado duro, pero también hemos disfrutado echándonos nuestras tapillas en el bar. Ha sido un auténtico placer trabajar con todos y cada uno de vosotros. A Elena Pita, por animar siempre el Departamento con ese tono de voz que te caracteriza, contigo en el Departamento no se aburre uno nunca. Y a Juamni, por su positivismo y alegría que hace que un mal día sea bueno. A Paqui, Puri, Cruz, Maribel y Galo por ayudarme siempre de buen grado en todo lo que me hiciera falta, y sobre todo por hacerme sentir como si estuviera en mi casa. Y muy especialmente a Aureliano, tu ausencia ha sido y será irreparable para toda la gente que te hemos conocido A Carmen, por su atención y alegría cuando he necesitado algo del Instituto de Neurociencias. A mis compañeros y amigos de otros laboratorios: Jesús y Raquel, Irene, Mohammed, Jorge y Víctor (el super-reventado). Por esos ratillos de charla que tenemos cuando nos encontramos en el desayuno o en cualquier pasillo de la Facultad y que nos sirven para compartir nuevas penas y alegrías. Y por esas cervecillas que nos hemos tomado en el bar y las que nos quedan. A Rosa Montes, por sus clases magistrales y supervisión acerca de las rutas del dolor, vaya tardes que te he dado ¿eh?. A mis padres y hermana, por apoyarme siempre durante estos años (a veces sé que no ha sido fácil aguantarme) y por hacerme ver que siempre puedo contar con vosotros. A mis padres, particularmente, por vuestra confianza y esfuerzo que habéis realizado para que yo pudiera llegar hasta aquí. También, agradeceros el enseñarme a esforzarme para alcanzar mis objetivos, siempre dando ejemplo de ello. Y a mi hermana por echarme una mano cuando me ha hecho falta. A toda mi familia en general y a mi tío Kisko en particular, por estar tan orgulloso de mí y por animarme siempre a seguir adelante. A los Nuño, por ser una familia ejemplar para mi y por su interés y apoyo constante durante estos años. A mis amigos de Huétor Tájar: Negro y Mari, Juanjo, Moli, Choco, Falo, Luisito, Morty, Campa, Cuartiyo, Roldan, Paqui, Ali…. A todos ellos y a los que no he podido nombrar, agradecerles todo su apoyo y compañía ya que sin ellos todo esto hubiera sido mucho más difícil. Bueno amigos, este es el resultado de todos estos años en los que no entendíais lo que hacía, que no sólo era matar ratones. A mis amigos de Bioquímica: Luizo y Sergio (el Loa) por interesaros siempre por cómo iba mi Tesis. A todos y cada uno de mis compañeros de piso con los que he estado conviviendo durante todos estos años (Christian, Loli, Juanlu, Edu, Triple, Karlangas…) A Vero (Pichu), una persona muy importante en esta Tesis, ya que desde que la conocí me ha mostrado su apoyo y ha estado a mi lado en los momentos difíciles, animándome y dándome fuerzas para seguir adelante. Gracias por ser como eres y parte de esta Tesis es tuya. A todos los becarios del resto de España que he tenido el placer de conocer durante esos inolvidables congresos de la SEF. A Karen Shashok y Richard, por revisar el inglés de esta Tesis. A la Fundación Hospital Clínico y al Instituto de Neurociencias de la Universidad de Granada, por la ayuda recibida para los gastos de encuadernación de esta Tesis. Por último, pero no por ello menos importante, quiero agradecer a todos los ratoncillos que han participado, aunque involuntariamente, en el desarrollo de este trabajo de investigación. Sin ellos no habría sido posible la realización de esta Tesis. Acknowledgements To Dr. David Finn, for the guidance and all that I have learnt from him throughout the period that I spent in the National University of Ireland in Galway. To Haruky, Horacio, Manuel and Ainara. They made my stay in Galway very comfortable. To Professor Cervero, for leading and guiding me. It was an honour to work in your lab in the McGill University of Montreal. To Ted Price, Raúl Sanoja and Mark Pitcher. For being so friendly with me and for the time that we shared working in Dr.
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