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    [Show abstract] [Hide abstract] 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 osteoarthritis we used in vivo electrophysiology to assess the effects of the Nav1.7 and Nav 1.8 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 behavioural 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 (0)C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8 - 60g and 48(0)C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40- 48(0)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(0)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 vF60g and 45(0)C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45(0)C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA treated group suggest an increased role of Nav 1.7 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. Copyright © 2015. Published by Elsevier Ltd.
    Full-text available · Article · Mar 2015 · Neuroscience
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    [Show abstract] [Hide abstract] ABSTRACT: The snake neurotoxin α-bungarotoxin (α-Bgtx) is a competitive antagonist at nicotinic acetylcholine receptors (nAChRs) and is widely used to study their function and cell-surface expression. Increasingly, α-Bgtx is also used as an imaging tool for fluorophore-labeling studies, and given the structural conservation within the pentameric ligand-gated ion channel family, we assessed whether α-Bgtx could bind to recombinant and native γ-aminobutyric type-A receptors (GABAARs). Applying fluorophore-linked α-Bgtx to recombinant αxβ1/2γ2 GABAARs expressed in HEK-293 cells enabled clear cell-surface labelling of α2β1/2γ2 contrasting with the weaker staining of α1/4β1/2γ2, and no labelling for α3/5/6β1/2γ2. The labelling of α2β2γ2 was abolished by bicuculline, a competitive antagonist at GABAARs, and by d-tubocurarine (d-Tc), which acts in a similar manner at nAChRs and GABAARs. Labelling by α-Bgtx was also reduced by GABA, suggesting that the GABA binding site at the receptor β-α subunit interface forms part of the α-Bgtx binding site. Using whole-cell recording, high concentrations of α-Bgtx (20 μM) inhibited GABA-activated currents at all αxβ2γ2 receptors examined, but at lower concentrations (5 μM), α-Bgtx was selective for α2β2γ2. Using α-Bgtx, at low concentrations, permitted the selective inhibition of α2 subunit-containing GABAARs in hippocampal dentate gyrus granule cells, reducing synaptic current amplitudes without affecting the GABA-mediated tonic current. In conclusion, α-Bgtx can act as an inhibitor at recombinant and native GABAARs and may be used as a selective tool to inhibit phasic but not tonic currents in the hippocampus.
    Full-text available · Article · Jan 2015 · Neuropharmacology
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    [Show abstract] [Hide abstract] ABSTRACT: Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerable side effects. The right central nucleus of the amygdala (CeA) is critical for the lateral spinal ascending pain pathway, regulates descending pain pathways and is key in the emotional-affective components of pain. Few studies have investigated the pharmacology of limbic brain areas in pain models. Here we determined the actions of systemic tapentadol on right CeA neurones of animals with neuropathy and which component of tapentadol contributes to its effect. Neuronal responses to multimodal peripheral stimulation of animals with spinal nerve ligation or sham surgery were recorded before and after two doses of tapentadol. After the higher dose of tapentadol either naloxone or yohimbine were administered. Systemic tapentadol resulted in dose-dependent decrease in right CeA neuronal activity only in neuropathy. Both naloxone and yohimbine reversed this effect to an extent that was modality selective. The interactions of the components of tapentadol are not limited to the synergy between the MOR and α2-adrenoceptors seen at spinal levels, but are seen at this supraspinal site where suppression of responses may relate to the ability of the drug to alter affective components of pain.
    Full-text available · Article · Jan 2015 · European Journal of Pharmacology
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