Modulation of Voltage-Gated Sodium Channels by Activation of Tumor Necrosis Factor Receptor-1 and Receptor-2 in Small DRG Neurons of Rats.
Tumor necrosis factor- (TNF-) α is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain. Its effects are mediated by two receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors play a crucial role in the sensitization of voltage-gated sodium channels (VGSCs), a key mechanism in the pathogenesis of chronic pain. Using the whole-cell patch-clamp technique, we examined the influence of TNFR-1 and TNFR-2 on VGSCs and TTX-resistant NaV1.8 channels in isolated rat dorsal root ganglion neurons by using selective TNFR agonists. The TNFR-1 agonist R32W (10 pg/mL) caused an increase in the VGSC current (I(Na(V))) by 27.2 ± 5.1%, while the TNFR-2 agonist D145 (10 pg/mL) increased the current by 44.9 ± 2.6%. This effect was dose dependent. Treating isolated NaV1.8 with R32W (100 pg/mL) resulted in an increase in I(NaV(1.8)) by 18.9 ± 1.6%, while treatment with D145 (100 pg/mL) increased the current by 14.5 ± 3.7%. Based on the current-voltage relationship, 10 pg of R32W or D145 led to an increase in I(Na(V)) in a bell-shaped, voltage-dependent manner with a maximum effect at -30 mV. The effects of TNFR activation on VGSCs promote excitation in primary afferent neurons and this might explain the sensitization mechanisms associated with neuropathic and inflammatory pain.
Department of Neurology, University of Duisburg-Essen, Germany.
M
M
Leo
Department of Neurology, University of Duisburg-Essen, Germany.
S
S
Argalski
Department of Neurology, University of Duisburg-Essen, Germany.
M
M
Schäfers
Department of Neurology, University of Duisburg-Essen, Germany.
T
T
Hagenacker
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000187:drug effects*; D009437:Neuralgia / Q000188:drug therapy; D009474:Neurons / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000819:agonists / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D016207:Cytokines; D062559:NAV1.8 Voltage-Gated Sodium Channel; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C568319:Scn10a protein, rat; C506237:Tnfrsf1a protein, rat; D014409:Tumor Necrosis Factor-alpha; D061566:Voltage-Gated Sodium Channels