Functional up-regulation of Nav 1.8 sodium channel in A[beta] afferent fibers subjected to chronic peripheral inflammation

• Published in: Journal of neuroinflammation Vol. 11
• Main Authors: Belkouch, Mounir, Dansereau, Marc-André, Tétreault, Pascal, Biet, Michael, Beaudet, Nicolas, Dumaine, Robert, Chraibi, Ahmed, Mélik-Parsadaniantz, Stéphane, Sarret, Philippe
• Format: Journal Article
• Language: English
• Published: London BioMed Central 01.01.2014
• Subjects: Behavior; Experiments; Medical research; Neurons; Pain; Rodents; Studies
• ISSN: 1742-2094
• DOI: 10.1186/1742-2094-11-45

Doc number: 45 Abstract Background: Functional alterations in the properties of Aβ afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Nav 1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Nav 1.8 in controlling Aβ-fiber excitability following persistent inflammation. Methods: Distribution and expression of Nav 1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund's adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Nav 1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Nav 1.8-preferring blocker on the electrophysiological properties of Nav 1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats. Results: Our findings revealed that Nav 1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Nav 1.8 peak current densities are enhanced in inflamed large myelinated Aβ-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in Aβ-fiber neuron excitability by shifting the voltage-dependent activation of Nav 1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Nav 1.8 currents in Aβ-fiber neurons observed following intraplantar CFA injection and concomitantly blocks CFA-induced mechanical allodynia, suggesting that Nav 1.8 regulation in Aβ-fibers contributes to inflammatory pain. Conclusions: Collectively, these findings support a key role for Nav 1.8 in controlling the excitability of Aβ-fibers and its potential contribution to the development of mechanical allodynia under persistent inflammation.