Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels

Abstract

Previously, we have characterized the capsaicin-insensitive low pH-sensitive (caps−lpH+) subtype of small-sized nociceptive dorsal root ganglion (DRG) neurons that express acid-sensing ion channels, T-type Ca2+ channels, and have isolectin B4-negative phenotype. These neurons demonstrated increased excitability in a model of long-term diabetes, contributing to chronic pain sensation. Here we studied changes in the excitability of the caps−lpH+ neurons and underlying changes in the functional expression and gating properties of ion channels under complete Freund's adjuvant (CFA)-induced peripheral inflammation. We have found that, under these pathological conditions, the functional expression of the acid-sensing ion channels (ASICs) and voltage-gated Na+ channels, was increased. In addition, T-type Ca2+ current was significantly increased in the neurons at the membrane potentials close to its resting value. Altogether, the observed changes in the channel functioning shifted a pH level evoking an action potential (AP) toward its physiological value and led to an increase of evoked and spontaneous excitability of the caps−lpH+ neurons that may contribute to hyperalgesia and chronic inflammatory pain.

In vitro characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease

“…4 A,B). In addition, the threshold potential, directly reflecting excitability of neurons [ 18 ], showed no difference between S126G and control neurons ( Fig. 4 C) while the same was true for the resting membrane potential ( Fig.…”

“…We not only aimed to uncover potential abnormalities reflecting current nerve pathology, but also to predict neuronal dysfunction associated with a putative late-onset phenotype. Rheobase, threshold potential, and resting membrane potential as key parameters reflecting membrane excitability [ 18 , 41 , 46 ] were not different compared to controls ( Fig. 4 ).…”

Diabetes-Induced Amplification of Nociceptive DRG Neuron Output by Upregulation of Somatic T-Type Ca2+ Channels

“…Aps simulated in a model containing a set of the above-described channels in response to a short (1 ms) threshold current stimulation are shown in Figure 1 H. Note that the inclusion of T-channels in the model resulted in a prominent afterdepolarization potential (ADP) experimentally observed in the caps- neurons [ 8 , 29 ].…”

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

“…This is contrasting with the peptidergic subpopulation, in which more than 60% of neurons express the ASIC3 mRNA and approximately 25% express ASIC1a and ASIC1b mRNAs [ 189 ]. An increased expression of ASICs is associated with an increase in evoked and spontaneous excitability of small size nociceptor neurons, which may contribute to hyperalgesia and chronic inflammatory pain [ 191 , 192 , 193 ].…”