Leff GP, González HNE, Matus OME, Pavón RL, Téllez SC, Salazar JA, Antón PB

Idioma: Español
Referencias bibliográficas: 234
Paginas: 179-196
Archivo PDF: 407.70 Kb.

RESUMEN

Este artículo resume varios aspectos de las múltiples actividades biológicas, celulares, efectos farmacológicos, respuestas fisiológicas y conductuales de dos nuevas sustancias peptídicas de naturaleza opioide, descubiertas recientemente y denominadas endomorfinas. Las endomorfinas son dos péptidos opioides, clasificados como endomorfina-1 (EM1, Tyr-Pro-Trp-Phe-NH₂) y endomorfina-2 (EM2, Tyr-Pro-Phe-Phe-NH₂), cuyas secuencias peptídicas fueron identificadas y aisladas del cerebro de bovino y humano por el grupo de Zadina en 1997. Estudios de unión radioligando-receptor demostraron que estos péptidos se unen con alta afinidad de unión al receptor opioide µ en relación con su capacidad de unión a otros subtipos de receptores opioides (kappa [κ], delta [δ]), previamente identificados en el SNC de mamíferos. Ambos péptidos están compuestos por cuatro aminoácidos y son estructuralmente distintos de las demás sustancias opioides endógenas conocidas.
Esta revisión detalla con precisión diversos aspectos de la farmacología y actividades celulares de estos opioides y sus implicaciones en la modulación de distintas circuitos o vías neurales y funcionamiento del SNC de los mamíferos, respectivamente. Los estudios relacionados con la función estructura-actividad de estos péptidos han mostrado que, al igual que la mayoría de los péptidos bioactivos endógenos de naturaleza opioide y no opioide, son vulnerables a la escisión peptídica por cortes enzimáticos mediante la exposición a distintas enzimas proteolíticas que pudiesen participar en la degradación endógena de las endomorfinas, y la obtención de diversos productos de degradación. Asimismo, este artículo menciona la amplia distribución neuroanatómica que poseen las endomorfinas en distintas regiones del cerebro, particularmente en aquellas que regulan el procesamiento y la transmisión de la información nociceptiva y que, por tanto, reflejan el papel potencial de estos péptidos en procesos fisiológicos de analgesia, entre muchos otros (memoria y otro aprendizaje). En este contexto, diferentes estudios basados en el empleo de ensayos inmunológicos (radioinmunoensayos [RIA] y técnicas de inmunohistoquímica [IHC]) que requieren el uso de anticuerpos específicos generados contra las secuencias consenso de las endomorfinas mostraron una amplia distribución de material inmunoreactivo a endomorfina (vg., EM1-LI, EM2-LI) en tejidos neurales de humano, bovino y roedores. Por ejemplo, la EM1-LI mostró una distribución relativamente abundante en una gran mayoría de las regiones del SNC de mamíferos estudiados, particularmente en la región rostral y superior del tallo cerebral, así como en el núcleo accumbens (NAc), la corteza prefrontal y frontal (PFCx), la amígdala (AMG), el tálamo (TH), el hipotálamo (HPT), el estriado (CPu) y fibras nerviosas de la raíz del ganglio dorsal (DRG). En contraste, la expresión de EMZ mostró ser muy abundante en la región de la médula espinal y en la región caudal del tallo cerebral.
La distribución de material inmunoreactivo a EM1-2 en el SNC de mamíferos mostró similitudes en cuanto a la distribución neuroanatómica reportada para otros péptidos opioides endógenos, previamente identificados (vg., encefalinas, dinorfinas, endorfinas). Así mismo, estudios paralelos lograron identificar la presencia de EM1-2-LI en órganos periféricos (vg., bazo, timo, células inflamatorias del tipo de macrófagos-monocitos, linfocitos y leucocitos PMN) y en plasma. Más aún, diversos estudios farmacológicos han mostrado que las actividades biológicas y respuestas fisiológicas de las EM1-2 están mediadas a través de la estimulación de los subtipos de receptores opioides µ1 y µ2. Estudios de inmunohistoquímica (IHC) demostraron la colocalización del receptor opioide µ y las EM1-2 en diversas regiones del SNC de mamiferos. Esto ha permitido proponer que las EM1-2 representan una nueva familia de péptidos opioides con funciones neuromoduladoras relevantes en el SNC, las cuales intervienen en la regulación de los procesos biológicos de percepción del dolor; respuestas de estrés; funciones límbicas de placer y recompensa inducidas por incentivos naturales y/o sustancias psicotrópicas; funciones de estado de alerta y vigilia, funciones cognitivas (de aprendizaje y memoria) y actividades de regulación neuroendócrina.
Además, diversos estudios celulares han mostrado que ambos péptidos opioides son capaces de inducir la internalización aguda o endocitosis del receptor opioide μ en células somáticas transfectadas con el ADN (ADNc) que codifica este mismo receptor opioide. Al igual que otros péptidos opioides (v.g., encefalinas), diversos estudios mostraron el catabolismo enzimático de estos péptidos amidados mediante la actividad de enzimas proteolíticas (v.g., carboxipeptidasa Y, aminopeptidasa M), lo que ha permitido sugerir que estos péptidos opioides son degradados por rutas de degradación enzimática similares que rigen para múltiples péptidos bioactivos moduladores en el SNC de los mamíferos. Al igual que otros péptidos endógenos, ambas endomorfinas mostraron la capacidad de modular la liberación neuronal de neurotransmisores (DA, NA, 5-HT, ACh) y hormonas peptídicas en áreas específicas del cerebro de los mamíferos. Asimismo, ambos péptidos mostraron una capacidad de generar efectos antinociceptivos potentes en forma dosis-dependiente posterior a su administración ICV o IT en animales experimentales, además de generar respuestas de tolerancia cruzada entre ambas endomorfinas y/o entre la EM1 y alcaloides opiáceos del tipo de la morfina.

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