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.2015 Jun 4:295:103-16.
doi: 10.1016/j.neuroscience.2015.03.042. Epub 2015 Mar 25.

Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat

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Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat

W Rahman et al. Neuroscience..

Abstract

Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48°C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48°C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48°C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48°C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45°C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45°C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in osteoarthritic pain.

Keywords: dorsal horn; electrophysiology; osteoarthritis; pain; sodium channels.

Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Figures

Fig. 1
Fig. 1
Neuronal responses evoked by vF 8–60 g and 45 and 48 °C heat stimulation and were significantly reduced by ProTxII in the MIA group only. Comparison of the effects of spinal administration of ProTxII (0.005 and 0.05 μg/50 μl) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham (n = 8, left panel) and MIA (n = 7, right panel) rats.§Denotes significance at 0.005 μg, and∗denotes significance at 0.05 μg compared with pre-drug baseline control data,p < 0.05, two-way RM ANOVA with Bonferroni test for multiple paired comparisons. Values are mean ± SEM.
Fig. 2
Fig. 2
Neuronal responses evoked by brush, vF 8–60 g and 48 °C heat were significantly inhibited after spinal administration of A-803467 in the MIA group. Comparison of the effects of topical spinal administration of A-803467 (10 and 50 μg/50 μl) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham (n = 6, left panel) and MIA (n = 7, right panel) rats. Asterisks and bars denote statistically significant main effect (one-way RM ANOVA).§Denotes significance at 10 μg,∗denotes significance at 50 μg compared with baseline control data,p < 0.05, two-way RM ANOVA with Bonferroni test for multiple paired comparisons. Values are mean ± SEM.
Fig. 3
Fig. 3
Neuronal responses evoked by brush, vF 26 and 60 g and 40 and 45 °C heat were significantly inhibited after systemic administration of A-803467 in the MIA group only. Comparison of the effects of systemic administration of A-803467 (3 and 30 mg/kg) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham (n = 7, left panel) and MIA (n = 7, right panel) rats.∗Denotes significance at 30 mg/kg compared with baseline control data,p < 0.05, two-way RM ANOVA with Bonferroni test for multiple paired comparisons. Values are mean ± SEM.
Fig. 4
Fig. 4
Intraplantar administration of A-80347 significantly reduced the Aδ-, C-fiber, post-discharge, Input, Wind-up, brush, vF 8–60 g and 45 and 48 °C heat evoked neuronal responses in the MIA group. Comparison of the effects of intraplantar administration of A-803467 (10 and 50 μg/50 μl) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham (n = 6, left panel) and MIA (n = 7, right panel) rats.§Denotes significance at 10 μg,∗denotes significance at 50 μg compared with baseline control data,p < 0.05, one-way or two-way RM ANOVA with Bonferroni test for multiple paired comparisons. Values are mean ± SEM.
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