RESUMEN
Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Neuroma , Miembro Fantasma , Animales , Humanos , Ratas , Masculino , Miembro Fantasma/fisiopatología , Miembro Fantasma/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/fisiología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales , Dolor Postoperatorio , Amputación QuirúrgicaRESUMEN
El cuerpo carotídeo (CC) es el principal quimiorreceptor arterial periférico, capaz de sensar los cambios en la PaO2, la PaCO2 y de pH y transducirlos en señales nerviosas reguladoras de respuestas ventilatorias, circulatorias y endócrinas, que permiten una adaptación a la hipoxemia, la acidosis y la hipercapnia. El seno carotídeo, ubicado próximo al CC, con función barorreceptora, genera respuestas cardiovasculares que descienden la tensión arterial (TA). Ambas estructuras son inervadas por el nervio del seno carotídeo (NSC), que a su vez se proyecta al núcleo del tracto solitario (NTS), y se relacionan íntimamente entre sí y reciben la denominación de baroquimiorreceptores. Últimamente estos órganos se han considerado claves en la regulación de respuestas cardiorrespiratorias homeostáticas que podrían estar íntimamente relacionadas con el desarrollo y el mantenimiento de la hipertensión arterial (HTA). Existe escasa información sobre los cambios estructurales que ocurren en estos órganos durante la HTA y/o como consecuencia de ella. Nuestro planteo es que los baroquimiorreceptores carotídeos representarían un nuevo órgano blanco de la HTA. En diversos estudios realizados en seres humanos y en modelos de hipertensión sistólica en animales observamos un daño severo en el CC que se correlacionó significativamente con la elevación de la TA. A su vez, considerando que el sistema renina-angiotensina-aldosterona (SRAA) tendría un papel significativo en la fisiopatología del daño observado, demostramos que el ramipril, versus el atenolol, ejerce un efecto protector sobre el CC más allá de la mera reducción de la TA. Incluso el losartán mostró dicho efecto protector, aun cuando los animales utilizados en los modelos fueron normotensos. Nuestros hallazgos indican que el CC se comporta como un órgano blanco de la HTA y que la activación de un SRAA local sería responsable de los cambios morfológicos y funcionales observados.
The carotid body (CB) is the main peripheral arterial chemoreceptor, able to sense changes in PaO2, PaCO2 and pH, and translate them into nervous signals that regulate ventilating, circulating and endocrine responses which allow adaptation to hypoxemia, acidosis, and hypercapnia. The carotid sinus, located next to the CB, with a baroreceptor function, generates cardiovascular responses that decrease arterial hypertension. Both structures are innervated by the carotid sinus nerve (CSN), which is projected to the solitary tract nucleus (STN), closely inter-related and called barochemoreceptors. Lately, these organs have been considered key in the regulation of homeostatic cardiorespiratory responses that could be intimately related to the development and maintenance of arterial hypertension (AHT). There is scant information on the structural changes that occur in these organs during AHT and/or as its consequence. Our hypothesis is that carotid barochemoreceptors would be a new target organ of the AHT. In several studies performed in humans and in models of systolic hypertension in animals we observed a severe damage in the CB which was significantly correlated with elevation of the AT. Hence, considering that the renin-angiotensin-aldosterone system(RAAS) would play a significant role in the pathophysiology of the observed injury, we showed that ramipril versus atenolol has a protective effect on the CB further to the mere decrease of the AT. Even though the animal models used had normal pressure, losartan showed this protective effect. Our findings indicate that the CB behaves as a target organ in AHT and the activation of a local RAAS would be responsible for the morphological and functional changes that were observed.