Biology subjects

Alles, S. R. A.

Publications and source records attributed to Alles, S. R. A..

3 recordsLinked to original sources

bioRxiv2024

Neuroimmune mechanisms of a mouse model of chronic back pain

Chronic back pain (CBP) is the leading cause of disability affecting 1 in 10 people worldwide. Symptoms are marked by persistent lower back pain, reduced mobility, and heightened cold sensitivity. Here, we utilize a mouse model of CBP induced by injecting urokinase-type plasminogen activator (uPA), a proinflammatory agent in the fibrinolytic pathway, between the L2/L3 lumbar vertebrae. We identified neuroimmune interactions contributing to uPA-induced CBP (henceforth, uPA-CBP) in mouse dorsal root ganglia (DRG), where nociceptive neurons reside. Flow cytometric data reveal that uPA-CBP increases CD45+CD11b+ cells in the DRG, a population characteristically implicated in other chronic pain models1. Blocking colony stimulating factor 1 receptor (CSF1R) signaling using PLX5622 partially reduced pain, suggesting CD45+CD11b+ macrophage involvement. Whole-cell patch-clamp electrophysiology data indicated DRG neuron hyperexcitability in CBP mice compared to controls. RNA sequencing revealed upregulation of pain- and inflammation-related genes involved in leukocyte migration. Together, these findings underscore the importance of the DRG neuroimmune axis in mediating chronic back pain. HighlightsO_LIuPA-CBP induces gait changes, mechanical and thermal sensitivity compared to shams C_LIO_LIuPA-CBP mice show increased CD45+CD11b+ cells in DRG compared to shams C_LIO_LIuPA-CBP mice show neuronal excitability in DRG neurons compared to shams C_LIO_LIPain behaviors are alleviated by pharmacologically blocking CSF1R signaling C_LIO_LIDysregulation of inflammation- and ion channel-related genes in uPA-CBP DRG C_LI

neuroscience↗

bioRxiv2020

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5-6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of silent neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.

neuroscience↗

bioRxiv2019

Sensory neuron-derived Nav1.7 contributes to dorsal horn neuron excitability

Expression of the voltage-gated sodium channel Nav1.7 in sensory neurons is required for pain sensation. We examined the role of Nav1.7 in the dorsal horn of the spinal cord using an epitope-tagged knock-in mouse. Immuno-electron microscopy showed the presence of Nav1.7 in dendrites of lamina II neurons, despite the absence of mRNA. Peripheral nervous system-specific Nav1.7 KO mice showed central deficits with lamina II dorsal horn tonic firing neurons more than halved and single spiking neurons more than doubled. Nav1.7 blocker PF05089771 diminished excitability in dorsal horn neurons, but had no effect on Nav1.7 KO mice. These data demonstrate an unsuspected functional role of peripherally generated Nav1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis.

neuroscience↗