The Effects of TNF‐α on TTX Resistant NaV Current in Muscle Dorsal Root Ganglion Neurons after Femoral Artery Occlusion

Abstract

Background/AimFemoral artery occlusion in rats has been used to study human peripheral artery disease (PAD). Using this animal model, a recent study suggests that increases of TNF‐α and its receptor lead to the exaggerated responses of sympathetic nervous activity and arterial blood pressure as metabolically sensitive muscle afferents are activated. Note that NaV1.8 channels are predominately presented in chemically sensitive thin fiber sensory nerves. The purpose of this study was to examine the role played by TNF‐α in regulating activity of NaV1.8 currents in muscle dorsal root ganglion (DRG) neurons of rats with PAD induced by femoral artery occlusion.MethodsDRG neurons from control and occluded limbs of rats were labelled by injecting the fluorescence tracer DiI into the hindlimb muscles five days prior to the experiments. A voltage patch clamp mode was used to examine TTX‐resistance (TTX‐R) NaV currents.ResultsSeventy‐two hours of femoral artery occlusion increased peak amplitude of TTX‐R and NaV1.8 currents in muscle DRG neurons. Likewise, after application of A803467 blocking NaV1.8 component of TTX‐R, TTX‐R currents were attenuated to a greater degree in DRG neurons of occluded limbs than in DRG neurons of control limbs. The inhibitory effects of A803467 on TTX‐R currents in muscle DRG neurons were 59 ± 2% in control and 75 ± 5% after occlusion (P<0.05 between two groups; n=6 in each group). TNF‐α exposure amplified TTX‐R and NaV1.8 currents in DRG neurons of control limbs and occluded limbs in a dose‐dependent manner. Notably, amplification of TTX‐R and NaV1.8 currents induced by TNF‐α was attenuated in DRG neurons with pre‐incubation of respective inhibitors of intracellular signal pathways p38‐MAPK, JNK and ERK.ConclusionOur data suggest that NaV1.8 is engaged in the role of TNF‐α in amplifying muscle afferent inputs as the hindlimb muscles are ischemic; and p38‐MAPK, JNK and ERK pathways are likely necessary to mediate the effects of TNF‐α.Support or Funding InformationThis study was supported by NIH P01 HL134609 & R01 HL141198