title: Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat.
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.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: w.rahman@ucl.ac.uk.
authors.forename: W
authors.initials: W
authors.lastname: Rahman
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000814:Aniline Compounds / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality; D005663:Furans / Q000627:therapeutic use; D006930:Hyperalgesia / Q000503:physiopathology; D007796:Laminectomy; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000627:therapeutic use*
chemical_list: C520740:A 803467; D000700:Analgesics; D000814:Aniline Compounds; D005663:Furans; D062556:NAV1.7 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers
keywords: dorsal horn; electrophysiology; osteoarthritis; pain; sodium channels
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