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,A.H Dickenson

doi:10.1016/j.neuroscience.2015.03.042

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.

Highlights

Osteoarthritis (OA) constitutes one of the largest cost burdens to healthcare in the western world with pain being the dominant symptom and reason for clinical presentation (Hiligsmann et al, 2013; Neogi, 2013)
Comparison of the average baseline pre-drug responses for monosodium iodoacetate (MIA) and shams per drug and per route of administration revealed a significantly greater C-fiber and von Frey (vF) 60 g evoked response in the MIA group vs sham in the ProTxII study (p < 0.05 Mann–Whitney test, Fig. 1 a vs b); a significantly greater response evoked by 40 °C stimulation in the MIA vs sham group in the A-803467 ‘‘systemic’’ study (p < 0.05 Mann Whitney test, Fig. 3 a vs b) and a significantly greater response evoked by vF 8 g in the MIA vs sham group in the A-803467 ‘‘intraplantar’’ study (p < 0.05 Mann–Whitney test, Fig. 4 a vs b)
The therapeutic utility of sodium channel blockers are not traditionally recommended for the treatment of OA pain, but given the large peripheral drive that follows the development of OA alongside the evidence for abnormal firing in peripheral and central neurons in the arthritic condition, implicates a key role for voltagegated sodium channels (VGSCs) in mediating OA pain

Summary

Introduction

Osteoarthritis (OA) constitutes one of the largest cost burdens to healthcare in the western world with pain being the dominant symptom and reason for clinical presentation (Hiligsmann et al, 2013; Neogi, 2013). Non-steroidal anti-inflammatory drugs (NSAIDs) are first-line treatments, often in combination with paracetamol or opioids, but analgesic efficacy is largely modest at best at tolerable doses, or is hampered by significant adverse effects with dose escalation (Harvey and Hunter, 2010; Zhang et al, 2010a). For these reasons, many patients resort to total joint replacement to relieve their pain, yet chronic pain remains for a significant proportion (about 20–40%) of patients (Kirwan et al, 1994; Creamer et al, 1996; Ethgen et al, 2004). Abundant data exist showing that maladaptive changes in VGSCs are critical for mediating variety of chronic pain conditions in both animals and humans (Eijkelkamp et al, 2012; Dib-Hajj et al, 2013) modulating their activity is a rational strategy for chronic pain therapy

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