RESUMEN

Armed conflicts exacerbate public health challenges in Sub-Saharan Africa. Inequality across groups and poverty in rural areas can be an important factor in triggering local wars. This study investigates whether equitable distribution of public services by governments across urban and rural geographical regions reduces the risk of local wars initiated by armed groups in Sub-Saharan African countries. Does an equitable distribution of public services such as healthcare and clean water public services across regions decrease the risk of armed conflicts? Uneven distribution of public services can increase the risk of conflict by contributing to group grievances, rural poverty, and rent-seeking competition over government resources. Analyses of 39 Sub-Saharan African countries from 1947 to 2021 show that a one-standard deviation increase in equal access to public services by urban-rural location lowers the risk of armed conflict, a substantial 37 to 53 percent with consideration of a battery of control variables.

Asunto(s)

Conflictos Armados , Servicios de Salud , Población Rural , Población Urbana , Servicios de Salud/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Conflictos Armados/prevención & control , Conflictos Armados/estadística & datos numéricos , África del Sur del Sahara , Pobreza , Disparidades en Atención de Salud/estadística & datos numéricos , Modelos Estadísticos , Humanos

RESUMEN

Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits via both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.

Asunto(s)

Artritis Experimental/fisiopatología , Microglía/fisiología , Neuronas Aferentes/fisiología , Médula Espinal/fisiopatología , Adenosina Trifosfato/fisiología , Animales , Artralgia/terapia , Modelos Animales de Enfermedad , Femenino , Hiperalgesia/fisiopatología , Ácido Yodoacético/farmacología , Masculino , Ratas , Ratas Sprague-Dawley

RESUMEN

Chronic joint pain such as mechanical allodynia is the most debilitating symptom of arthritis, yet effective therapies are lacking. We identify the pannexin-1 (Panx1) channel as a therapeutic target for alleviating mechanical allodynia, a cardinal sign of arthritis. In rats, joint pain caused by intra-articular injection of monosodium iodoacetate (MIA) was associated with spinal adenosine 5'-triphosphate (ATP) release and a microglia-specific up-regulation of P2X7 receptors (P2X7Rs). Blockade of P2X7R or ablation of spinal microglia prevented and reversed mechanical allodynia. P2X7Rs drive Panx1 channel activation, and in rats with mechanical allodynia, Panx1 function was increased in spinal microglia. Specifically, microglial Panx1-mediated release of the proinflammatory cytokine interleukin-1ß (IL-1ß) induced mechanical allodynia in the MIA-injected hindlimb. Intrathecal administration of the Panx1-blocking peptide 10panx suppressed the aberrant discharge of spinal laminae I-II neurons evoked by innocuous mechanical hindpaw stimulation in arthritic rats. Furthermore, mice with a microglia-specific genetic deletion of Panx1 were protected from developing mechanical allodynia. Treatment with probenecid, a clinically used broad-spectrum Panx1 blocker, resulted in a striking attenuation of MIA-induced mechanical allodynia and normalized responses in the dynamic weight-bearing test, without affecting acute nociception. Probenecid reversal of mechanical allodynia was also observed in rats 13 weeks after anterior cruciate ligament transection, a model of posttraumatic osteoarthritis. Thus, Panx1-targeted therapy is a new mechanistic approach for alleviating joint pain.

Asunto(s)

Artralgia/prevención & control , Artritis Experimental/prevención & control , Conexinas/metabolismo , Conexinas/fisiología , Hiperalgesia/prevención & control , Microglía/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/fisiología , Enfermedades de la Médula Espinal/prevención & control , Animales , Artralgia/etiología , Artritis Experimental/etiología , Conexinas/genética , Hiperalgesia/etiología , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Ratas , Ratas Sprague-Dawley , Enfermedades de la Médula Espinal/etiología

RESUMEN

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

Asunto(s)

Conducta Animal/efectos de los fármacos , Conexinas/genética , Microglía/efectos de los fármacos , Morfina/efectos adversos , Narcóticos/efectos adversos , Proteínas del Tejido Nervioso/genética , Células del Asta Posterior/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/genética , Adenosina Trifosfato/metabolismo , Animales , Apirasa/farmacología , Western Blotting , Técnicas de Cultivo de Célula , Técnicas de Cocultivo , Conexinas/antagonistas & inhibidores , Conexinas/metabolismo , Mefloquina/farmacología , Ratones , Microglía/metabolismo , Naloxona/farmacología , Antagonistas de Narcóticos/efectos adversos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nocicepción/efectos de los fármacos , Células del Asta Posterior/metabolismo , Probenecid/farmacología , Ratas , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/metabolismo

RESUMEN

Autoimmune profiling in rats revealed the antioxidant enzyme, peroxiredoxin 6 (PRDX6), as a target for autoantibodies evoked in response to traumatic brain injury (TBI). Consistent with this proposal, immunohistochemical analysis of rat cerebral cortex demonstrated that PRDX6 is highly expressed in the perivascular space, presumably contained within astrocytic foot processes. Accordingly, an immunosorbent electrochemiluminescence assay was developed for investigating PRDX6 in human samples. PRDX6 was found to be measurable in human blood and highly expressed in human cerebral cortex and platelets. Circulating levels of PRDX6 were elevated fourfold over control values 4 to 24 h following mild-to-moderate TBI. These findings suggest that PRDX6 may serve as a biomarker for TBI and that autoimmune profiling is a viable strategy for the discovery of novel TBI biomarkers.

Asunto(s)

Autoinmunidad/genética , Biomarcadores/análisis , Lesiones Encefálicas/genética , Peroxiredoxina VI/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Plaquetas/metabolismo , Lesiones Encefálicas/diagnóstico , Corteza Cerebral/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mapeo Peptídico , Peroxiredoxina VI/análisis , Peroxiredoxina VI/sangre , Ratas , Ratas Sprague-Dawley , Adulto Joven

RESUMEN

Important challenges for the diagnosis and monitoring of mild traumatic brain injury (mTBI) include the development of plasma biomarkers for assessing neurologic injury, monitoring pathogenesis, and predicting vulnerability for the development of untoward neurologic outcomes. While several biomarker proteins have shown promise in this regard, used individually, these candidates lack adequate sensitivity and/or specificity for making a definitive diagnosis or identifying those at risk of subsequent pathology. The objective for this study was to evaluate a panel of six recognized and novel biomarker candidates for the assessment of TBI in adult patients. The biomarkers studied were selected on the basis of their relative brain-specificities and potentials to reflect distinct features of TBI mechanisms including (1) neuronal damage assessed by neuron-specific enolase (NSE) and brain derived neurotrophic factor (BDNF); (2) oxidative stress assessed by peroxiredoxin 6 (PRDX6); (3) glial damage and gliosis assessed by glial fibrillary acidic protein and S100 calcium binding protein beta (S100b); (4) immune activation assessed by monocyte chemoattractant protein 1/chemokine (C-C motif) ligand 2 (MCP1/CCL2); and (5) disruption of the intercellular adhesion apparatus assessed by intercellular adhesion protein-5 (ICAM-5). The combined fold-changes in plasma levels of PRDX6, S100b, MCP1, NSE, and BDNF resulted in the formulation of a TBI assessment score that identified mTBI with a receiver operating characteristic (ROC) area under the curve of 0.97, when compared to healthy controls. This research demonstrates that a profile of biomarker responses can be used to formulate a diagnostic score that is sensitive for the detection of mTBI. Ideally, this multivariate assessment strategy will be refined with additional biomarkers that can effectively assess the spectrum of TBI and identify those at particular risk for developing neuropathologies as consequence of a mTBI event.