Changes in the expression of Na V1.7, Na V1.8 and Na V1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain

Abstract

Voltage-gated sodium channels play an essential role in regulating the excitability of nociceptive primary afferent neurones. In particular the tetrodotoxin-sensitive (TTX-S) Na V1.7 and the tetrodotoxin-resistant (TTX-R) Na V1.8 and Na V1.9 channels have been suggested to play a role in inflammatory pain. Previous work has revealed acute administration of inflammatory mediators, such as Freund’s complete adjuvant (FCA) or carrageenan caused an upregulation in the levels of Na V1.7 and Na V1.8 protein in DRG (dorsal root ganglia) tissue up to 4 days post-insult. In the present study, the expression of Na V1.7, Na V1.8 and Na V1.9 was examined over a 28 day timecourse during a rat model of FCA-induced chronic inflammatory joint pain. Using the retrograde tracer Fast Blue (FB) and specific Na V1.7, Na V1.8 and Na V1.9 sodium channel antibodies, immunohistochemical staining techniques were used to study sodium channel expression in a distinct population of L3–L5 knee joint afferent DRGs. In the ganglia, counts were made of positively labelled cells in the FB population. The results demonstrate that, following FCA injection, Na V1.9 expression is upregulated at days 14, 21 and 28 post-FCA, with Na V1.7 and Na V1.8 showing increased channel expression at days 14 and 28. These observations are accompanied by a unilateral joint hypersensitivity in the FCA-injected knee indicated by a behavioural shift in weight distribution measured using an incapacitance tester. The increased presence of these channels suggests that Na V1.7, Na V1.8 and Na V1.9 play a role, at least in part, in the maintenance of chronic inflammatory pain several weeks after the initial insult.