Publication: El receptor α2 adrenérgico de la célula cromafín de la médula adrenal: ¿una nueva diana para el tratamiento del dolor neuropático?
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2018-11-13
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Universidad Complutense de Madrid
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Abstract
El dolor es el primer motivo de consulta en medicina humana. Puede ser un síntoma que alerta sobre la presencia de una enfermedad susceptible de tratamiento específico (dolor nociceptivo) o constituir una entidad patológica por sí misma (dolor neuropático), cuya característica fundamental es la alteración del procesamiento de la información nociceptiva. Si bien en el tratamiento del dolor nociceptivo el reto terapéutico consistiría actualmente en el logro de mayores niveles de seguridad de los fármacos analgésicos, en el tratamiento del dolor neuropático la situación actual viene marcada por la falta de eficacia. Existe pues un vacío terapéutico que demanda el desarrollo de nuevos fármacos que actúen sobre nuevas dianas terapéuticas. La hipótesis de partida de este trabajo fue la de considerar al dolor neuropático como un estresor capaz de originar una respuesta del sistema simpatoadrenomedular que, a su vez, contribuyera a la fenomenología dolorosa, cerrando así un círculo vicioso por el que el dolor y el estrés se alimentan de forma recíproca. Para ello hemos implementado la constricción crónica del nervio ciático de la rata como modelo experimental para la valoración de la alodinia mecánica y térmica como indicadores de dolor neuropático y consecuentemente la evaluación de fármacos potencialmente útiles en su tratamiento. Nuestros resultados indican que dicho modelo de dolor comporta un aumento de la actividad simpatoadrenomedular que se manifestaría por el aumento de la transmisión sináptica (aumento de la inervación colinérgica y de la frecuencia de corrientes excitadoras postsinápticas espontáneas; sEPSCs) en la unión nervio esplácnico-célula cromafín, una mayor expresión de receptores nicotínicos de membrana y el incremento de la exocitosis de catecolaminas por las células cromafines de la médula adrenal. Así mismo, la lesión del nervio ciático se asocia al aumento de la inervación catecolaminérgica en los ganglios espinales, el incremento de la excitabilidad de los somas de las neuronas nociceptivas primarias y el desarrollo de un tono adrenérgico algésico en la planta del pie de la extremidad afectada. Por otra parte, la administración sistémica de SKF29661, un inhibidor de la feniletanolamina-N-metiltransferasa (PNMT), ejerce un efecto antialodínico mecánico y térmico probablemente relacionado con la inhibición de la síntesis y liberación de adrenalina por las células cromafines de la médula adrenal...
Pain is the first reason for medical consultation in both human and veterinary medicine. It can be a symptom that alerts on the presence of a disease that can be specifically treated (nociceptive pain) or may constitute a pathological entity by itself (neuropathic pain), whose fundamental characteristic is the alteration of the processing of nociceptive information. While the therapeutic challenge in the treatment of nociceptive pain would be the attainment of higher levels of safety of the analgesic drugs, in the treatment of neuropathic pain the current situation is marked by the lack of effectiveness. There is therefore a therapeutic gap that demands the development of new drugs acting on new therapeutic targets. The starting hypothesis of this work was to consider neuropathic pain as a stressor capable of originating a response of the sympathoadrenomedullary system which, in turn, contributed to painful manifestations, hence closing a vicious circle whereby pain and stress feed to each other. To this end, we have implemented the chronic constriction injury (CCI) of the sciatic nerve of the rat as an experimental model for the evaluation of mechanical and thermal allodynia as indicators of neuropathic pain, and, consequently suitable for the evaluation of drugs potentially useful as analgesics. Our results indicate that the CCI model of neuropathic pain involves an increase in sympathoadrenal activity as manifested by the enhancement of synaptic transmission (denser cholinergic innervation and a higher frequency of spontaneous excitatory postsynaptic currents; sEPSCs) in the splanchnic nerve-chromaffin cell junction, increased expression of plasma membrane nicotinic receptors, and augmented catecholamine exocytosis by chromaffin cells of the adrenal medulla. Likewise, sciatic nerve injury is associated with an increased number of catecholaminergic fibers in dorsal root ganglia, a higher excitability of the soma of primary nociceptive neurons, and the development of an algogenic adrenergic tone in the plantar surface of the affected hindlimb. On the other hand, the systemic (I.P.) administration of SKF29661, a phenylethanolamine-N-methyl transferase (PNMT) inhibitor, exerts a mechanical and thermal antiallodynic effect that is probably related to the inhibition of the synthesis and release of adrenaline by chromaffin cells of the adrenal medulla...
Pain is the first reason for medical consultation in both human and veterinary medicine. It can be a symptom that alerts on the presence of a disease that can be specifically treated (nociceptive pain) or may constitute a pathological entity by itself (neuropathic pain), whose fundamental characteristic is the alteration of the processing of nociceptive information. While the therapeutic challenge in the treatment of nociceptive pain would be the attainment of higher levels of safety of the analgesic drugs, in the treatment of neuropathic pain the current situation is marked by the lack of effectiveness. There is therefore a therapeutic gap that demands the development of new drugs acting on new therapeutic targets. The starting hypothesis of this work was to consider neuropathic pain as a stressor capable of originating a response of the sympathoadrenomedullary system which, in turn, contributed to painful manifestations, hence closing a vicious circle whereby pain and stress feed to each other. To this end, we have implemented the chronic constriction injury (CCI) of the sciatic nerve of the rat as an experimental model for the evaluation of mechanical and thermal allodynia as indicators of neuropathic pain, and, consequently suitable for the evaluation of drugs potentially useful as analgesics. Our results indicate that the CCI model of neuropathic pain involves an increase in sympathoadrenal activity as manifested by the enhancement of synaptic transmission (denser cholinergic innervation and a higher frequency of spontaneous excitatory postsynaptic currents; sEPSCs) in the splanchnic nerve-chromaffin cell junction, increased expression of plasma membrane nicotinic receptors, and augmented catecholamine exocytosis by chromaffin cells of the adrenal medulla. Likewise, sciatic nerve injury is associated with an increased number of catecholaminergic fibers in dorsal root ganglia, a higher excitability of the soma of primary nociceptive neurons, and the development of an algogenic adrenergic tone in the plantar surface of the affected hindlimb. On the other hand, the systemic (I.P.) administration of SKF29661, a phenylethanolamine-N-methyl transferase (PNMT) inhibitor, exerts a mechanical and thermal antiallodynic effect that is probably related to the inhibition of the synthesis and release of adrenaline by chromaffin cells of the adrenal medulla...
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Tesis de la Universidad Complutense de Madrid, Facultad de Veterinaria, Departamento de Toxicología y Farmacología, leída el 23/06/2017