Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

Механизмы перехода от ритмической активности к пачечной в модели ноцицептивного нейрона

The transitions from tonic spiking to bursting for the nociceptive neuron model have been studied with changing the external stimulus value. The presence of the fold limit cycle bifurcation in the structure of the bifurcation diagram of the fast subsystem and the torus bifurcation in the structure of the bifurcation diagram of the full system lead to the emergence of special solutions of the type torus canards in these transitions. This confirms the assumption that torus canards are an obligatory feature for transitions between rhythmic and burst discharges

THE GABA-ERGIC SYSTEM DOES NOT CONTROL THE NOCICEPTIVE RESPONSES OF PRIMARY SENSORY NEURON

The aim of the study was to elucidate the molecular mechanisms of the interconnection of the GABA-ergic and nociceptive systems at the level of the peripheral division of the CNS. The data obtained indicate that GABA does not affect the activation gating device of the NaV1.8 channel of the primary sensory neuron responsible for coding pain signals.This agent in a wide range of concentrations also does not affect the growth of neurites of sensory neurons of embryonic nervous tissue. These results confirm our assumption, expressed earlier that the asynaptic membrane of the primary nociceptive neuron is not under the control of the GABA-ergic system.

Нелинейная динамика паттернов импульсной активности ноцицептивных нейронов при коррекции повреждающего болевого воздействия

A bifurcation analysis of a nociceptive neuron model was performed to study how the firing activity pattern changes when an antinociceptive response to damaging pain stimulation arises in rat dorsal ganglia. Ectopic train activity was found to arise in the model. Suppression of train activity was demonstrated to proceed solely through modification of the activation gating structure of the Na _ V 1.8 slow sodium channel in response to comenic acid, which exerts an analgesic effect and is an active ingredient of the new nonopioid analgesic Anoceptin.