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The Effects of TNF‐α on TTX Resistant Na V Current in Muscle Dorsal Root Ganglion Neurons after Femoral Artery Occlusion
Author(s) -
Li Qin,
Qin Lu,
Li Jianhua
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03287
Subject(s) - dorsal root ganglion , medicine , femoral artery , anatomy , occlusion , ganglion , chemistry , anesthesia , endocrinology , dorsum
Background/Aim Femoral 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 Na V 1.8 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 Na V 1.8 currents in muscle dorsal root ganglion (DRG) neurons of rats with PAD induced by femoral artery occlusion. Methods DRG 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) Na V currents. Results Seventy‐two hours of femoral artery occlusion increased peak amplitude of TTX‐R and Na V 1.8 currents in muscle DRG neurons. Likewise, after application of A803467 blocking Na V 1.8 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 Na V 1.8 currents in DRG neurons of control limbs and occluded limbs in a dose‐dependent manner. Notably, amplification of TTX‐R and Na V 1.8 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. Conclusion Our data suggest that Na V 1.8 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 Information This study was supported by NIH P01 HL134609 & R01 HL141198