SEXUAL DIFFERENCES IN COMORBIDITY CHRONIC PAIN AND ANXIETY: FOCUS ON THE LOCUS COERULEUS (Q3134436): Difference between revisions
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Revision as of 11:54, 10 October 2021
Project Q3134436 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | SEXUAL DIFFERENCES IN COMORBIDITY CHRONIC PAIN AND ANXIETY: FOCUS ON THE LOCUS COERULEUS |
Project Q3134436 in Spain |
Statements
188,760.0 Euro
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235,950.0 Euro
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80.0 percent
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1 January 2019
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31 December 2022
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UNIVERSIDAD DE CADIZ
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36°29'40.92"N, 6°16'2.50"W
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11012
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ACTUALMENTE EL DOLOR CRONICO ES CONSIDERADO UN FACTOR PRECIPITANTE PARA SUFRIR ANSIEDAD Y DEPRESION, ASI COMO CIERTOS TRASTORNOS COGNITIVOS. ES RELEVANTE DESTACAR QUE ESTOS TRASTORNOS SE DAN CON MAYOR PREVALENCIA EN LAS MUJERES, SUGIRIENDO UN PAPEL RELEVANTE DEL SEXO. SON NECESARIOS BIOMARCADORES QUE PUEDAN PREDECIR ESTA COMORBILIDAD Y RESULTA IMPERATIVO INNOVAR EN TRATAMIENTOS QUE PUEDAN FRENAR EL PASO DE UNA ENTIDAD A OTRA EVITANDO LA CRONICIDAD. ASI, ES INELUDIBLE INVESTIGAR LOS MECANISMOS NEUROBIOLOGICOS QUE SUBYACEN EN ESTA COMORBILIDAD PARA SABER COMO INTERRUMPIR EL CIRCULO VICIOSO DOLOR¿DEFICIENTE SALUD MENTAL, ASI COMO CONOCER SI EXISTE UNA BASE NEUROBIOLOGICA DIFERENCIAL ENTRE HOMBRES Y MUJERES._x000D_ _x000D_ ESTUDIOS PRECLINICOS HAN DEMOSTRADO QUE LA INDUCCION DE DOLOR EXPERIMENTAL (DOLOR NEUROPATICO) CONLLEVA A QUE LOS ANIMALES (ROEDORES) MUESTREN COMPORTAMIENTOS DE TIPO ANSIOSO, DEPRESIVO Y DEFICIT COGNITIVO A LO LARGO DEL TIEMPO, SUGIRIENDO QUE EL TIEMPO ES UN FACTOR CRITICO Y PROVEYENDONOS DE UNA HERRAMIENTA EXPERIMENTAL. SIN EMBARGO, NO EXISTEN HASTA EL MOMENTO ESTUDIOS BASICOS SOBRE LAS POSIBLES DIFERENCIAS ENTRE HEMBRAS Y MACHOS EN EL DESARROLLO DE ANSIDEDAD/DEPRESION/DEFICIT COGNITIVO DERIVADOS DEL DOLOR CRONICO. POR TANTO, LAS DIFERENCIAS EN RELACION AL SEXO CONSTITUIRA UN OBJETIVO DE CARACTER TRANSVERSAL EN NUESTRO PROYECTO. NOS CENTRAREMOS EN EL LOCUS COERULEUS (LC), UNA ESTRUCTURA SEXUALMENTE DIMORFICA, QUE PODRIA ACTUAR COMO NEXO PARA LA TRANSMISION DEL DOLOR, ENTRE LA MEDULA ESPINAL Y AREAS CORTICOLIMBICAS QUE PODRIA SER CRITICA PARA EL DESARROLLO DE LAS PATOLOGIAS MENTALES ASOCIADAS. EN NUESTRO ANTERIOR PROYECTO HEMOS DEMOSTRADO QUE SINTOMAS CONCRETOS DEL DOLOR ESTAN MEDIADOS POR REGIONES DEL LC ESPECIFICAS SUGIRIENDO QUE EL LC POSEE UNA ORGANIZACION MODULAR. ASI, LOS ESTADOS DE DOLOR A LARGO PLAZO CONDUCEN A UNA HIPERACTIVACION DE LA VIA NORADRENERGICA DESDE EL LC HACIA LA AMIGDALA BASOLATERAL (BLA) QUE NO ESTA RELACIONADO CON EL UMBRAL SENSORIAL. LA HIPERACTIVACION DE ESTA VIA CONDUCIRIA A ESTADOS ANSIOSOS ASI COMO A UN AUMENTO DEL APRENDIZAJE Y LA MEMORIA DE CONTENIDO EMOCIONAL NEGATIVO. ESTOS DATOS NOS LLEVAN A INTENTAR, EN EL PRESENTE PROYECTO, DISCERNIR LOS CIRCUITOS IMPLICADOS EN LA ANSIEDAD DERIVADA DEL DOLOR CRONICO. PARA LLEVAR A CABO ESTE FIN VAMOS A IDENTIFICAR HISTOLOGICAMENTE CONEXIONES MONOSINAPTICAS CON EL CIRCUITO LC-BLA MEDIANTE LA TECNOLOGIA (CTRIO). TENIENDO EN CUENTA NUESTROS DATOS, PROPONEMOS QUE EXISTIRA UNA HIPERACTIVACION DE LAS NEURONAS CRF QUE VAN DESDE EL NUCLEO PARAGIGANTOCELULAR (PGI) HACIA LC-BLA, YA QUE EL PGI ES EL MAYOR EFERENTE EXCITATORIO AL LC Y TRANSMITE LA INFORMACION SENSORIAL DESDE LA MEDULA ESPINAL. POSTERIORMENTE USAREMOS MANIPULACIONES FARMACOGENETICAS (DESIGNER RECEPTORS EXCLUSIVELY ACTIVATED BY DESIGNER DRUGS, DREADDS) PARA FUNCIONALMENTE EVALUAR ESTAS VIAS EN RATONES (TH-CRE Y CRF-CRE). POR OTRO LADO, PRENTENDEMOS ENCONTRAR UN BIOMARCADOR ESPECIFICO DE LA FUNCION DEL LC EN CONDIONES DE SALUD Y ENFERMEDAD. EL DIAMETRO PUPILAR HA SIDO RECIENTEMENTE PROPUESTO COMO UN POSIBLE CANDITO. ASI, EVALUAREMOS LA RELACION EXISTENTE ENTRE EL TAMAÑO DE LA PUPILA Y LA ACTIVADAD ESPONTENEA Y EVOCADA (ELECTRICAMENTE/OPTOGENETICAMENTE) DEL LC. ASIMISMO, ESTUDIAREMOS LA RELACION DE LA ACTIVIDAD DE LAS VIAS PGI-LC-BLA Y EL DIAMETRO PUPILAR CON EL FIN DE IDENTIFICAR UN BIOMARCADOR DE COMORBILIDAD DOLOR CRONICO-ANSIEDAD TANTO EN MACHOS COMO HEMBRAS. (Spanish)
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CHRONIC PAIN IS CURRENTLY CONSIDERED AS A PRECIPITANT FACTOR FOR SUFFERING ANXIETY, DEPRESSION, AS WELL AS CERTAIN COGNITIVE DISORDERS. IMPORTANTLY, THESE NEUROPSYCHIATRIC DISEASES ARE MORE PREVALENT IN FEMALES COMPARED WITH MALES, POINTING TOWARD MAJOR SEX DIFFERENCES. THUS, IT IS NEEDED TO FIND BIOMARKERS THAT CAN PREDICT THIS COMORBIDITY, AND IT IS IMPERATIVE TO INNOVATE TREATMENTS THAT CAN DISRUPT THE PASSAGE FROM ONE ENTITY TO ANOTHER, AVOIDING CHRONICITY. IT IS INDISPENSABLE INVESTIGATE THE UNDERLYING NEUROBIOLOGICAL MECHANISMS OF THIS COMORBIDITY TO KNOW HOW TO DISCONTINUE THE CIRCLE CHRONIC PAIN ¿ POOR MENTAL HEALTH STATUS, AS WELL AS, TO KNOW WETHER THERE IS A NEUROBIOLOGICAL BASES UNDERLYING SEX DIFFERENCES._x000D_ _x000D_ PRECLINICAL STUDIES HAVE SHOWN THAT PAIN INDUCTION (NEUROPATHIC PAIN) LEADS TO ANXIODEPRESSIVE BEHAVIORS AND COGNITIVE IMPAIRMENT ALONG THE TIME. THIS SUGGESTS THAT TIME IS A CRITICAL FACTOR FOR THESE MENTAL DISORDERS BUT ALSO THAT RESEARCHERS HAVE A VALIDATED EXPERIMENTAL TOOL. HOWEVER, UP TO NOW THE VAST MAJORITY OF ANIMAL STUDIES IN THIS FIELD HAVE BEEN PERFORMED IN MALES. THUS, IT IS NECESSARY TO FURTHER CHARACTERIZE THE ANIMALS MODELS CONSIDERING SEXUAL DIFFERENCES (CROSS-CUTTING OBJECTIVE IN OUR PROJECT). WE WILL FOCUS IN THE LOCUS COERULEUS (LC), A SEXUALLY DIMORPHIC STRUCTURE, THAT COULD BE A CRITICAL LINK FOR PAIN TRANSMISSION FROM THE SPINAL CORD TO CORTICOLIMBIC AREAS AND THE SUBSEQUENT DEVELOPMENT OF COMORBID MENTAL DEFICITS IN NEUROPATHIC PAIN AND INTERESINGLY LC SEEMS TO BE A SEXUALLY DIMORPHIC STRUCTURE. WE HAVE FOUND IN OUR PREVIOUS PROJECT IN AN ANIMAL MODEL OF PAIN-INDUCED ANXIETY THAT THERE IS AN OVERACTIVATION OF THE PATHWAY FROM THE LC TO THE BASOLATERAL AMYGDALA (BLA) LEADING TO INCREASE ANXIETY AND EMOTIONAL FEAR LEARNING. HOWEVER, THE NEURONAL CIRCUITS OF HOW THIS IS PRODUCED IS LARGELY UNKNOWN. THEREFORE, WE PROPOSE TO EMPLOY A CELL-TYPE-SPECIFIC TRACING OF THE RELATIONSHIP BETWEEN INPUT AND OPUTPUT APPROACH, TO HISTOLOGICALLY IDENTIFY MONOSYNAPTIC CONNECTIONS TO NORADRENERGIC LC NEURONS PROJECTING TO BLA. THIS NEW INFORMATION WOULD HELP TO RESOLVED WHAT NEURONAL MECHANISMS DETERMINE THE GENERATION OF ANXIETY PHENOTYPE IN THE COMORBIDITY OF PAIN AND ANXIETY. WE HYPOTETHIZE THAT NORADRENERGIC NEURONS IN THE LC PROJECTING TO BLA ARE OVERACTIVATED DUE TO THE ACTIVATION OF THE SYNAPTIC INPUT FROM CORTICOTROPIN-RELEASING FACTOR (CRF) NEURONS FROM NUCLEUS PARAGIGANTOCELLULARIS (PGI). THE PGI IS THE MAJOR EXCITATORY AFFERENT TO THE LC CONVEYING NOCICEPTIVE INPUTS FROM THE SPINAL CORD. NEXT, WE WILL NEXT INTERROGATE THESE CIRCUITS USING CHEMOGENETIC MANIPULATIONS (DESIGNER RECEPTORS EXCLUSIVELY ACTIVATED BY DESIGNER DRUGS, DREADDS) IN MICE (TH-CRE Y CRF-CRE). ON THE OTHER HAND, RECENT FINDINGS EVIDENCE THAT PUPIL DIAMETER IS A RELIABLE MARKER OF LC ACTIVITY, SO WE HYPOTHESIZE THAT PUPILLOMETRY COULD BE A USEFUL NON-INVASIVE TECHNIQUE FOR LC ASSESSMENT, BOTH IN HEALTH AND PATHOLOGICAL CONDITIONS. IN THIS SENSE, WE PROPOSE TO EXPLORE IF LC SPECIFIC PROJECTIONS CONTRIBUTE TO PUPIL SIZE FLUCTUATIONS (PRIMARILY PGI-LC-BLA PATHWAY) WITH THE AIM OF DEVELOPING NEW BIOMARKERS FOR THE COMORBID OF CHRONIC PAIN AND ANXIETY BOTH IN MALES AND FEMALES. (English)
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Cádiz
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Identifiers
RTI2018-099778-B-I00
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