ABSTRACT
Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Subject(s)
Animals , Mice , Amputation, Surgical , Chronic Pain/pathology , Disease Models, Animal , Ganglia, Spinal/pathology , Hyperalgesia/etiology , Ion Channels/metabolism , Macrophages , Neuroma/pathologyABSTRACT
Las inyecciones epidurales de esteroides son frecuentemente indicadas en el sindrome radicular lumbosacro, producido por hernias de disco, protrusiones discales o estenosis del canal, cuando éste no responde al tratamiento no intervencionista. Sin embargo, por distintas causas, aproximadamente 20% de los pacientes no responden a estas inyecciones, quedando pocas opciones terapéuticas disponibles. La radiofrecuencia pulsada del Ganglio de la Raíz Dorsal de las raíces afectadas es una alternativa válida para tratar el sindrome cuando es refractario al tratamiento con inyecciones epidurales de esteroides, en caso de que la cirugía de columna no está indicada o se prefiera evitar. Se presenta un caso clínico de un sindrome radicular lumbosacro refractario, causado por protrusiones discales lumbares, donde se utilizó la radiofrecuencia pulsada del ganglio de la raíz dorsal con buenos resultados, evaluados mediante el Inventario Abreviado del Dolor (Brief Pain Inventory).
Lumbosacral radicular syndrome, produced by discs herniations, discs protrusions or spinal stenosis is frequently treated by injecting steroids in the epidural space. However, 20% of the patients are resistant to this treatment, so few therapeutics options for them are left. Pulsed radiofrequency of the Dorsal Root Ganglion is a validated therapeutic option, when the syndrome is refractory to epidural steroid injections and spinal surgery is not indicated or elected. We report a clinical case of a lumbosacral radicular syndrome, refractory to epidural steroid injections, successfully treated with pulsed radiofrequency of lumbar Dorsal Root Ganglion, utilizing the Spanish version of the Brief Pain Inventory, as an outcome evaluation tool.
Subject(s)
Humans , Radiculopathy/radiotherapy , Steroids/therapeutic use , Low Back Pain/radiotherapy , Pulsed Radiofrequency Treatment , Ganglia, Spinal/pathology , Lumbosacral Region/pathology , Injections, Epidural , Chronic DiseaseABSTRACT
A subset of patients of amyotrophic lateral sclerosis (ALS) present with mutation of Cu/Zn superoxide dismutase 1 (SOD1), and such mutants caused an ALS-like disorder when expressed in rodents. These findings implicated SOD1 in ALS pathogenesis and made the transgenic animals a widely used ALS model. However, previous studies of these animals have focused largely on motor neuron damage. We report herein that the spinal cords of mice expressing a human SOD1 mutant (hSOD1-G93A), besides showing typical destruction of motor neurons and axons, exhibit significant damage in the sensory system, including Wallerian-like degeneration in axons of dorsal root and dorsal funiculus, and mitochondrial damage in dorsal root ganglia neurons. Thus, hSOD1-G93A mutation causes both motor and sensory neuropathies, and as such the disease developed in the transgenic mice very closely resembles human ALS.
Subject(s)
Animals , Humans , Mice , Amyotrophic Lateral Sclerosis/enzymology , Axons/pathology , Disease Models, Animal , Ganglia, Spinal/pathology , Mice, Transgenic , Mitochondria/pathology , Motor Neurons/metabolism , Mutation , Nerve Degeneration/pathology , Sensory Receptor Cells/pathology , Spinal Cord/pathology , Superoxide Dismutase/geneticsABSTRACT
An in vitro model of adult dorsal root ganglion neurons infection by rabies virus is described. Viral marked neurotropism is observed, and the percentage and the degree of infection of the neurons is higher than in non neuronal cells, even if neurons are the minority of the cells in the culture. The neuritic tree is also heavily infected by the virus.