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Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks(More)
Ion permeation and channel opening are two fundamental properties of ion channels, the molecular bases of which are poorly understood. Channels can exist in two permeability states, open and closed. The relative amount of time a channel spends in the open conformation depends on the state of activation. In voltage-gated ion channels, activation involves(More)
Voltage-gated K channels assemble from four identical subunits symmetrically arranged around a central permeation pathway. Each subunit harbors a voltage-sensing domain. The sigmoidal nature of the activation kinetics suggests that multiple sensors need to undergo a conformational change before the channel can open. Following activation, individual K(More)
Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Na(v)1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Na(v)1.8 channel blockers. A-887826(More)
A single dose of the organophosphate insecticide O,O'-diethyl-O-3,5,6- trichloro-2-pyridylphosphorothioate [chlorpyrifos (CPF), 279 mg/kg, SC] caused extensive inhibition of cortical and striatal cholinesterase (ChE) activity in adult rats at 2 (94-96%), 4 (82-83%), and 6 (58-60%) weeks after treatment. These persistent changes in ChE activity were(More)
This study examined the effect of a 1 h, self-paced handcycling time trial on blood leukocytes, mucosal immunity, and markers of stress in paraplegic athletes. Nine male paraplegic athletes (spinal injury level thoracic 4-lumbar 2) performed 1 h of handcycling exercise on a standard 400 m athletics track. Heart rate (HR) was measured continuously during(More)
This study investigated the effect of crank configuration on muscle activity and torque production during submaximal arm crank ergometry. Thirteen non-specifically trained male participants volunteered. During the research trials they completed a warm-up at 15W before two 3-min exercise stages were completed at 50 and 100W; subjects used either a(More)
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective(More)
Cells maintain a negative resting membrane potential through the constitutive activity of background K+ channels. A novel multigene family of such K+ channels has recently been identified. A unique characteristic of these K+ channels is the presence of two homologous, subunit-like domains, each containing a pore-forming region. Sequence co-variations in the(More)
BACKGROUND AND PURPOSE NaV 1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav 1.8 channel blocker of novel chemotype. EXPERIMENTAL APPROACH The inhibition of Nav 1.8(More)