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BK channel & pain

Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C Lepore, Manuel Covarrubias
Presynaptic voltage-gated K+ (Kv) channels in dorsal root ganglion (DRG) neurons are thought to regulate nociceptive synaptic transmission in the spinal dorsal horn. However, the Kv channel subtypes responsible for this critical role have not been identified. The Kv3.4 channel is particularly important because it is robustly expressed in DRG nociceptors, where it regulates action potential (AP) duration. Furthermore, Kv3.4 dysfunction is implicated in the pathophysiology of neuropathic pain in multiple pain models...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Fang-Xiong Zhang, Vinicius M Gadotti, Ivana A Souza, Lina Chen, Gerald W Zamponi
Cavα2δ subunits contribute to the cell-surface expression of Cav2 calcium channels. Upregulation of Cavα2δ-1 in dorsal root ganglion neurons occurs after nerve injury and results in an increased synaptic abundance of Cav2.2 channels in the spinal dorsal horn, thus enhancing the transmission of pain signals. Here, we report that large conductance calcium-activated potassium (BK) channels interact with the Cavα2δ subunit. Coexpression of BK channels with the Cav2 calcium channels reduces their cell-surface expression and whole-cell current density by competing the Cavα2δ subunit away from the Cav2 complex...
February 20, 2018: Cell Reports
Graziela Vieira, Juliana Cavalli, Elaine C D Gonçalves, Tainara R Gonçalves, Larissa R Laurindo, Maíra Cola, Rafael C Dutra
Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw...
2017: Frontiers in Pharmacology
Robson Costa, Maíra A Bicca, Marianne N Manjavachi, Gabriela C Segat, Fabiana Chaves Dias, Elizabeth S Fernandes, João B Calixto
Kinin B1 (B1R) and B2 receptors (B2R) and the transient receptor potential vanilloid 4 (TRPV4) channel are known to play a critical role in the peripheral neuropathy induced by paclitaxel (PTX) in rodents. However, the downstream pathways activated by kinin receptors as well as the sensitizers of the TRPV4 channel involved in this process remain unknown. Herein, we investigated whether kinins sensitize TRPV4 channels in order to maintain PTX-induced peripheral neuropathy in mice. The mechanical hyperalgesia induced by bradykinin (BK, a B2R agonist) or des-Arg(9)-BK (DABK, a B1R agonist) was inhibited by the selective TRPV4 antagonist HC-067047...
March 10, 2017: Molecular Neurobiology
C Severini, P Petrocchi Passeri, M T Ciotti, F Florenzano, C Petrella, F Malerba, B Bruni, M D'Onofrio, I Arisi, R Brandi, R Possenti, P Calissano, A Cattaneo
Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease. However, the development of an NGF-based therapy is limited by its potent pain activity. We have developed a "painless" derivative form of human NGF (NGF61/100), characterized by identical neurotrophic properties but a reduced nociceptive sensitization activity in vivo. Here we characterized the response of rat dorsal root ganglia neurons (DRG) to the NGF derivative NGF61/100, in comparison to that of control NGF (NGF61), analyzing the expression of noxious pro-nociceptive mediators...
May 1, 2017: Neuropharmacology
Yoshinori Hayashi, Saori Morinaga, Jing Zhang, Yasushi Satoh, Andrea L Meredith, Takahiro Nakata, Zhou Wu, Shinichi Kohsaka, Kazuhide Inoue, Hiroshi Nakanishi
Although morphine is a gold standard medication, long-term opioid use is associated with serious side effects, such as morphine-induced hyperalgesia (MIH) and anti-nociceptive tolerance. Microglia-to-neuron signalling is critically involved in pain hypersensitivity. However, molecules that control microglial cellular state under chronic morphine treatment remain unknown. Here we show that the microglia-specific subtype of Ca(2+)-activated K(+) (BK) channel is responsible for generation of MIH and anti-nociceptive tolerance...
May 31, 2016: Nature Communications
C Contet, S P Goulding, D A Kuljis, A L Barth
Large conductance Ca(2+)- and voltage-activated K(+) (BK) channels are widely distributed in the postnatal central nervous system (CNS). BK channels play a pleiotropic role in regulating the activity of brain and spinal cord neural circuits by providing a negative feedback mechanism for local increases in intracellular Ca(2+) concentrations. In neurons, they regulate the timing and duration of K(+) influx such that they can either increase or decrease firing depending on the cellular context, and they can suppress neurotransmitter release from presynaptic terminals...
2016: International Review of Neurobiology
Dongyang Huang, Ce Liang, Fan Zhang, Hongchao Men, Xiaona Du, Nikita Gamper, Hailin Zhang
T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude...
April 29, 2016: Biochemical and Biophysical Research Communications
Jeremy M Thompson, Guangchen Ji, Volker Neugebauer
BACKGROUND: Arthritis pain is an important healthcare issue with significant emotional and affective consequences. Here we focus on potentially beneficial effects of activating small-conductance calcium-activated potassium (SK) channels in the amygdala, a brain center of emotions that plays an important role in central pain modulation and processing. SK channels have been reported to regulate neuronal activity in the central amygdala (CeA, output nucleus). We tested the effects of riluzole, a clinically available drug for the treatment of amyotrophic lateral sclerosis, for the following reasons...
August 28, 2015: Molecular Pain
Rebeca Caires, Enoch Luis, Francisco J Taberner, Gregorio Fernandez-Ballester, Antonio Ferrer-Montiel, Endre A Balazs, Ana Gomis, Carlos Belmonte, Elvira de la Peña
Hyaluronan (HA) is present in the extracellular matrix of all body tissues, including synovial fluid in joints, in which it behaves as a filter that buffers transmission of mechanical forces to nociceptor nerve endings thereby reducing pain. Using recombinant systems, mouse-cultured dorsal root ganglia (DRG) neurons and in vivo experiments, we found that HA also modulates polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channels. HA diminishes heat, pH and capsaicin (CAP) responses, thus reducing the opening probability of the channel by stabilizing its closed state...
2015: Nature Communications
Xuan Zhang, Huiran Zhang, Najing Zhou, Jiaxi Xu, Man Si, Zhanfeng Jia, Xiaona Du, Hailin Zhang
M/Kv7 K(+) channels, Ca(2+)-activated Cl(-) channels (CaCCs) and voltage gated Na(+) channels expressed in dorsal root ganglia (DRG) play an important role in nociception. Tannic acid has been proposed to be involved in multiple beneficial health effects; tannic acid has also been described to be analgesic. However the underlying mechanism is unknown. In this study, we investigated the effects of tannic acid on M/Kv7 K(+), Na(+) currents and CaCCs, and the effects on bradykinin-induced nociceptive behavior...
October 5, 2015: European Journal of Pharmacology
Ciara Doran, Jonathan Chetrit, Matthew C Holley, David Grundy, Mohammed A Nassar
In vitro cell lines from DRG neurons aid drug discovery because they can be used for early stage, high-throughput screens for drugs targeting pain pathways, with minimal dependence on animals. We have established a conditionally immortal DRG cell line from the Immortomouse. Using immunocytochemistry, RT-PCR and calcium microfluorimetry, we demonstrate that the cell line MED17.11 expresses markers of cells committed to the sensory neuron lineage. Within a few hours under differentiating conditions, MED17.11 cells extend processes and following seven days of differentiation, express markers of more mature DRG neurons, such as NaV1...
2015: PloS One
Kalina Szteyn, Ruben Gomez, Kelly A Berg, Nathaniel A Jeske
Endothelin-1 (ET-1) and bradykinin (BK) are endogenous peptides that signal through Gαq/11-protein coupled receptors (GPCRs) to produce nociceptor sensitization and pain. Both peptides activate phospholipase C to stimulate Ca(2+) accumulation, diacylglycerol production, and protein kinase C activation and are rapidly desensitized via a G-protein receptor kinase 2-dependent mechanism. However, ET-1 produces a greater response and longer lasting nocifensive behavior than BK in multiple models, indicating a potentially divergent signaling mechanism in primary afferent sensory neurons...
March 2015: ASN Neuro
Yueming Zheng, Haiyan Xu, Li Zhan, Xindi Zhou, Xueqin Chen, Zhaobing Gao
Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK)...
June 2015: Pain
J Li, B Xue, T Han, K Huang, L Gong, X Ma, K Liu, S Cui, M Zhang, W Kunze, C Liu
BACKGROUND: Oxytocin plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of oxytocin analgesia, but little is known about whether peripheral mechanisms are also involved. METHODS: The mesenteric afferent discharge was recorded in vitro. The expressions of oxytocin receptor (OTR) and neuronal nitric oxide synthase (nNOS) in longitudinal muscle myenteric plexus (LMMP) was identified by immunofluorescence...
January 2015: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Xiaona Du, Han Hao, Sylvain Gigout, Dongyang Huang, Yuehui Yang, Li Li, Caixue Wang, Danielle Sundt, David B Jaffe, Hailin Zhang, Nikita Gamper
Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission...
November 2014: Pain
Andrew J Castiglioni, Jaime García-Añoveros
Genetic and molecular searches in animals identify two families of ion channels used by specialized mechanosensory cells. These are the degenerin/epithelial Na+ channels (Deg/ENaCs) and transient receptor potential (TRP) channels. Some of these channels open in response to mechanical forces and/or mediate cellular responses to mechanical stimulation. TRPA1 is expressed in nociceptive neurons of peripheral ganglia and in the sensory epithelia of the inner ear. In nociceptors, TRPA1 forms chemosensitive channels that mediate the response to exogenous pain-producing chemicals as well as to the endogenous proalgesic bradykinin (BK)...
2007: Current Topics in Membranes
James R F Hockley, George Boundouki, Vincent Cibert-Goton, Cian McGuire, Ping K Yip, Christopher Chan, Michael Tranter, John N Wood, Mohammed A Nassar, L Ashley Blackshaw, Qasim Aziz, Gregory J Michael, Mark D Baker, Wendy J Winchester, Charles H Knowles, David C Bulmer
Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal adverse effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitization of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually...
October 2014: Pain
Rainer H Straub
Chronic inflammatory diseases are accompanied by a systemic response of the body, necessary to redirect energy-rich fuels to the activated immune system and to induce volume expansion. The systemic response is switched on by two major pathways: (a) circulating cytokines enter the brain, and (b) signals via sensory nerve fibers are transmitted to the brain. Concerning item b, sensory nerve terminals are equipped with a multitude of receptors that sense temperature, inflammation, osmolality, and pain. Thus, they can be important to inform the brain about peripheral inflammation...
September 2014: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Irene Samengo, Diego Currò, Vincenzo Barrese, Maurizio Taglialatela, Maria Martire
Large conductance, calcium-activated potassium channels [big potassium (BK) channel] consist of a tetramer of pore-forming α-subunit and distinct accessory β-subunits (β1-4) that modify the channel's properties. In this study, we analyzed the effects of BK channel activators and blockers on glutamate and γ-aminobutyric acid (GABA) release from synaptosomes isolated from the cerebral cortices or trigeminal caudal nuclei (TCN) of rats. Real-time polymerase chain reaction was used to characterize BK channel α and β(1-4) subunit expression in the cortex and in the trigeminal ganglia (TG), whose neurons project primary terminal afferents into the TCN...
May 2014: Neurochemical Research
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