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BK channel & pain

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...
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...
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
Zainul Amiruddin Zakaria, Mohd Hijaz Mohd Sani, Manraj Singh Cheema, Arifah Abdul Kader, Teh Lay Kek, Mohd Zaki Salleh
BACKGROUND: Muntingia calabura (Elaecoparceae) is a medicinal plant traditionally used, particularly, by the Peruvian people to alleviate headache and cold, pain associated with gastric ulcers or to reduce the prostate gland swelling. Following the recent establishment of antinociceptive activity of M. calabura leaf, the present study was performed to further elucidate on the possible mechanisms of antinociception involved. METHODS: The methanol extract of M. calabura (MEMC) was prepared in the doses of 100, 250 and 500 mg/kg...
2014: BMC Complementary and Alternative Medicine
Byeongjun Lee, Hawon Cho, Jooyoung Jung, Young Duk Yang, Dong-Jin Yang, Uhtaek Oh
BACKGROUND: Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception...
2014: Molecular Pain
Ying Wu, Yongfeng Liu, Panpan Hou, Zonghe Yan, Wenjuan Kong, Beiying Liu, Xia Li, Jing Yao, Yuexuan Zhang, Feng Qin, Jiuping Ding
The transient receptor potential vanilloid receptor 1 (TRPV1) channel is a nonselective cation channel activated by a variety of exogenous and endogenous physical and chemical stimuli, such as temperature (≥42 °C), capsaicin, a pungent compound in hot chili peppers, and allyl isothiocyanate. Large-conductance calcium- and voltage-activated potassium (BK) channels regulate the electric activities and neurotransmitter releases in excitable cells, responding to changes in membrane potentials and elevation of cytosolic calcium ions (Ca(2+))...
2013: PloS One
Erika K Lippoldt, Russell R Elmes, Daniel D McCoy, Wendy M Knowlton, David D McKemy
Chronic pain associated with injury or disease can result from dysfunction of sensory afferents whereby the threshold for activation of pain-sensing neurons (nociceptors) is lowered. Neurotrophic factors control nociceptor development and survival, but also induce sensitization through activation of their cognate receptors, attributable, in part, to the modulation of ion channel function. Thermal pain is mediated by channels of the transient receptor potential (TRP) family, including the cold and menthol receptor TRPM8...
July 24, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Viktor Lukacs, Yevgen Yudin, Gerald R Hammond, Esseim Sharma, Kiyoko Fukami, Tibor Rohacs
Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca(2+)-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides...
July 10, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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