a-803467 and Pain

a-803467 has been researched along with Pain* in 11 studies

Reviews

1 review(s) available for a-803467 and Pain

ArticleYear
Sodium channel blockers.
    Journal of medicinal chemistry, 2007, May-31, Volume: 50, Issue:11

    Topics: Analgesics; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Anticonvulsants; Benzyl Compounds; Cyclopentanes; Humans; Ion Channel Gating; Pain; Peripheral Nervous System Diseases; Pyrimidines; Semicarbazones; Sodium Channel Blockers; Sodium Channels

2007

Other Studies

10 other study(ies) available for a-803467 and Pain

ArticleYear
Contribution of platelet P2Y
    Journal of thrombosis and haemostasis : JTH, 2017, Volume: 15, Issue:6

    Essentials The role of platelet P2Y. Background P2Y

    Topics: Adenosine Monophosphate; Aniline Compounds; Animals; Blood Platelets; Chemokine CXCL1; Chronic Pain; Cytokines; Freund's Adjuvant; Furans; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Receptors, Purinergic P2Y12; Time Factors; Tumor Necrosis Factor-alpha

2017
Functional up-regulation of Nav1.8 sodium channel on dorsal root ganglia neurons contributes to the induction of scorpion sting pain.
    Acta biochimica et biophysica Sinica, 2016, Volume: 48, Issue:2

    BmK I, purified from the venom of scorpion Buthus martensi Karsch (BmK), is a receptor site-3-specific modulator of voltage-gated sodium channels (VGSCs) and can induce pain-related behaviors in rats. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 contributes to most of the sodium current underlying the action potential upstroke in dorsal root ganglia (DRG) neurons and may serve as a critical ion channel targeted by BmK I. Herein, using electrophysiological, molecular, and behavioral approaches, we investigated whether the aberrant expression of Nav1.8 in DRG contributes to generation of pain induced by BmK I. The expression of Nav1.8 was found to be significantly increased at both mRNA and protein levels following intraplantar injection of BmK I in rats. In addition, the current density of TTX-R Nav1.8 sodium channel is significantly increased and the gating kinetics of Nav1.8 is also altered in DRG neurons from BmK I-treated rats. Furthermore, spontaneous pain and mechanical allodynia, but not thermal hyperalgesia induced by BmK I, are significantly alleviated through either blockade of the Nav1.8 sodium channel by its selective blocker A-803467 or knockdown of the Nav1.8 expression in DRG by antisense oligodeoxynucleotide (AS-ODN) targeting Nav1.8 in rats. Finally, BmK I was shown to induce enhanced pain behaviors in complete freund's adjuvant (CFA)-inflamed rats, which was partly due to the over-expression of Nav1.8 in DRG. Our results suggest that functional up-regulation of Nav1.8 channel on DRG neurons contributes to the development of BmK I-induced pain in rats.

    Topics: Aniline Compounds; Animals; Freund's Adjuvant; Furans; Ganglia, Spinal; Gene Knockdown Techniques; Injections, Spinal; Ion Channel Gating; Kinetics; Male; Models, Neurological; NAV1.8 Voltage-Gated Sodium Channel; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Scorpion Stings; Scorpion Venoms; Sensory Receptor Cells; Sodium Channel Blockers; Up-Regulation

2016
Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research.
    Molecular therapy : the journal of the American Society of Gene Therapy, 2014, Volume: 22, Issue:8

    The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell-derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders.

    Topics: Aniline Compounds; Cell Differentiation; Cells, Cultured; Colforsin; Furans; Ganglia, Spinal; Gene Expression Regulation; Humans; Ion Channels; Pain; Pluripotent Stem Cells; Sensory Receptor Cells; Single-Cell Analysis

2014
Functional upregulation of nav1.8 sodium channels on the membrane of dorsal root Ganglia neurons contributes to the development of cancer-induced bone pain.
    PloS one, 2014, Volume: 9, Issue:12

    We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin-resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain.

    Topics: Aniline Compounds; Animals; Bone Neoplasms; Cell Line, Tumor; Cell Membrane; Electrophysiological Phenomena; Female; Furans; Ganglia, Spinal; Gene Expression Regulation, Neoplastic; Hyperalgesia; NAV1.8 Voltage-Gated Sodium Channel; Neurons; Pain; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Up-Regulation

2014
The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia.
    Anesthesia and analgesia, 2012, Volume: 114, Issue:1

    It has been reported that the selective blockade of Nav1.8 sodium channels could be a possible target for the development of analgesics without unwanted side effects. However, the precise role of spinal Nav1.8 in the induction and maintenance of persistent pain, e.g., mechanical allodynia (MA) and thermal hyperalgesia (TH), is not clear. We designed this study to investigate whether spinal Nav1.8 contributes to capsaicin-induced and peripheral ischemia-induced MA and TH.. The Nav1.8 blockers, A-803467 or ambroxol, were injected intrathecally either before or after intraplantar capsaicin injection. To evaluate capsaicin-induced neuronal activation in the spinal cord, we quantified the number of Fos-immunoreactive cells in the dorsal horn. In the thrombus-induced ischemic pain model, we determined the differential effect of A-803467 on the induction phase or maintenance phase of MA.. Intrathecal injection of A-803467 (10, 30, 100 nmol) or ambroxol (241, 724, 2410 nmol) before intraplantar injection of capsaicin dose dependently prevented the induction of both MA and TH. However, posttreatment with A-803467 (100 nmol) and ambroxol (2410 nmol) did not reduce the MA that had already developed, but did significantly suppress capsaicin-induced TH. Moreover, the capsaicin-induced increase of spinal Fos-immunoreactive cells was significantly diminished by pretreatment, but not posttreatment with Nav1.8 blockers. In thrombus-induced ischemic pain rats, repetitive treatments of A-803467 during the induction period also prevented the development of MA, whereas A-803467 treatments during the maintenance period were ineffective in preventing or reducing MA.. These results demonstrate that spinal activation of Nav1.8 mediates the early induction of MA, but not the maintenance of MA. However, both the induction and maintenance of TH are modulated by the intrathecal injection of Nav1.8 blockers. These findings suggest that early treatment with a Nav1.8 blocker can be an important factor in the clinical management of chronic MA associated with inflammatory and ischemic pain.

    Topics: Ambroxol; Aniline Compounds; Animals; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Furans; Hot Temperature; Hyperalgesia; Injections, Spinal; Ischemia; Male; NAV1.8 Voltage-Gated Sodium Channel; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Spinal Cord; Time Factors

2012
Additive antinociceptive effects of the selective Nav1.8 blocker A-803467 and selective TRPV1 antagonists in rat inflammatory and neuropathic pain models.
    The journal of pain, 2009, Volume: 10, Issue:3

    Evidence implicating Nav1.8 and TRPV1 ion channels in various chronic pain states is extensive. In this study, we used isobolographic analysis to examine the in vivo effects of the combination of the Nav1.8 blocker A-803467 [5-(4-Chloro-phenyl)-furan-2-carboxylic acid (3,5-dimethoxy-phenyl)-amide] with 2 structurally distinct TRPV1 antagonists, A-840257 [1-(1H-Indazol-4-yl)-3-([R]-4-piperidin-1-yl-indan-1-yl)-urea] or A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]. The antinociceptive effects of the Nav1.8 blocker alone and in combination with each TRPV1 antagonist were examined in an inflammatory (complete Freund's adjuvant, CFA) and a neuropathic (spinal nerve ligation, SNL) pain model after systemic (intraperitoneal) administration. Alone, A-803467 was efficacious in both CFA and SNL models with ED(50) values of 70 (54.2 to 95.8) mg/kg and 70 (38.1 to 111.9) mg/kg, respectively. The ED(50) values of the TRPV1 antagonists A-840257 and A-425619 alone in the CFA model were 10 (3.6 to 14.9) mg/kg and 43 (24.1 to 62.2) mg/kg, respectively; both were without significant effect in the SNL model. A series of experiments incorporating 1:1, 3:1, or 0.3:1 ED(50) dose-ratio combinations of A-840257 and A-803467, or A-425619 and A-803467 were performed in both pain models, and the effective doses of mixtures that produced 50% antinociception (ED(50, mix)) were determined by isobolographic analysis. The ED(50, mix) in each case was not found to be statistically different than ED(50, add), the theoretical ED(50) calculated assuming additive effects. These data demonstrate that Nav1.8 blockers and TRPV1 antagonists administered in combination produce an additive effect in rat pain models. Using such a combination strategy to produce analgesia may potentially provide an improved therapeutic separation from unwanted in vivo side effects associated with blockade of either Nav1.8 or TRPV1 alone.. In this report, effects of coadministration of TRPV1 antagonists and A-803467, a Nav1.8 blocker, were investigated in preclinical rodent models of neuropathic and inflammatory pain. The 2 classes of novel antinociceptive agents produced an additive interaction in attenuating CFA-induced thermal hyperalgesia, providing a rationale for their use as a combination strategy in the clinic for treating inflammatory pain.

    Topics: Analgesics; Aniline Compounds; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Freund's Adjuvant; Furans; Inflammation; Isoquinolines; Male; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sodium Channels; Spinal Nerves; Substance-Related Disorders; Treatment Outcome; TRPV Cation Channels; Urea

2009
Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.
    Journal of medicinal chemistry, 2008, Feb-14, Volume: 51, Issue:3

    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 blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.

    Topics: Amides; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cricetinae; Cricetulus; Furans; Ganglia, Spinal; Humans; In Vitro Techniques; Male; Mice; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurons; Pain; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sodium Channel Blockers; Sodium Channels; Structure-Activity Relationship

2008
A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats.
    The Journal of pharmacology and experimental therapeutics, 2008, Volume: 324, Issue:3

    We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Na(v)1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10-30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30-100 nmol/1 mul) or into the hindpaw receptive field (300 nmol/50 mul) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50-150 nmol/0.5 mul) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Na(v)1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Na(v)1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.

    Topics: Aniline Compounds; Animals; Furans; Male; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Spinal Nerves; Synaptic Transmission

2008
A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat.
    Proceedings of the National Academy of Sciences of the United States of America, 2007, May-15, Volume: 104, Issue:20

    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 tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

    Topics: Action Potentials; Analgesics; Aniline Compounds; Animals; Capsaicin; Evoked Potentials; Furans; Ganglia, Spinal; Humans; Inflammation; Kinetics; Male; Mononeuropathies; NAV1.8 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurons; Pain; Pain Management; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sodium Channel Blockers; Sodium Channels

2007
Painful research: identification of a small-molecule inhibitor that selectively targets Nav1.8 sodium channels.
    Molecular interventions, 2007, Volume: 7, Issue:4

    Voltage-gated sodium channels in nociceptive neurons are attractive targets for novel pain therapeutics. Although drugs that target voltage-gated sodium channels have proven value as pain therapeutics, the drugs that are currently available are non-specific sodium channel inhibitors, which limit their usefulness. Recently, a selective small-molecule inhibitor of Na(v)1.8, a voltage-gated sodium channel isoform that participates in peripheral pain mechanisms, has been developed. This exciting new compound shows efficacy in several animal models of pain and is anticipated to be only the first of many new isoform-specific sodium channel blockers.

    Topics: Aniline Compounds; Animals; Furans; Humans; NAV1.8 Voltage-Gated Sodium Channel; Neurons; Nociceptors; Pain; Protein Isoforms; Sodium Channel Blockers; Sodium Channels

2007