The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability

Abstract

Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.

The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors

“…The enhancement of g Na(v)1.9 under pathological conditions has been shown to lead to activation of nociceptive neurons (Baker, 2005; Amaya et al, 2006; Binshtok et al, 2008; Maingret et al, 2008; Gudes et al, 2015). We examined the ability of ${\text{g}}_{\text{Kv}7/\text{M}}^{\text{Terminal}}$ to prevent spontaneous activity when g Na(v)1.9 was enhanced.…”

“…First, the model validation was performed by simulating a single-compartment DRG soma-like 25μm X 25 μm cylinder model (Gudes et al, 2015) with a membrane capacitance of 1μF cm −2 and membrane resistance of 10000 Ω cm −2 . The simulated resting potential was −57.85 mV, which fits our experimental results (−58.15±0.9 mV).…”

Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation

“…In agreement, TNFα induced inflammatory pain in vivo is dependent on both TNFR1 and prostaglandins [30,36]. TNFα also induces rapid modulation of nociceptor sensitivity by p38MAPK mediated phosphorylation of Nav1.8 and Na v 1.9 sodium channels to alter neuron excitability [33,37,38]. In a model of cancer-related pain, TNFα acted via TNFR2 to increase TRPV1 expression resulting in thermal hyperalgesia [39].…”

Ultrafast optical recording reveals distinct capsaicin-induced ion dynamics along single nociceptive neurite terminals in vitro

“…DRG culture preparation: Adult mice were deeply anesthetized (3% isoflurane), and DRG were isolated and dissociated in a manner similar to that described previously, 15 with the following modifications: dissected ganglia were placed in ice-cold DMEM (Biological Industries), pelleted, and reconstituted for enzymatic digestion in solution containing 5 mg∕ml collagenase and 1 mg∕ml dispase II (Roche) for 45 min. Cells were triturated in the presence of 50 U DNase I (Sigma) and centrifuged through 10% bovine serum albumin (Sigma).…”

“…Many molecular and biophysical aspects of nociception have been described using nociceptor cell bodies, situated in dorsal root ganglions (DRG) or trigeminal ganglions. [13][14][15][16] The functional environment [17][18][19] and geometry of terminals differ from that of cell bodies, and likely, their passive membrane properties, density, and specific repertoire of transducer and voltage-gated channels. Hence, detailed characterization of ion signal onset, kinetics, and magnitude, along the terminals and terminal axons, have yet to be achieved, albeit being highly valuable for understanding nociceptive physiology.…”