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Tal Hoffmann, Katrin Kistner, Richard W Carr, Mohammed A Nassar, Peter W Reeh, Christian Weidner
The upregulation of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 has previously been associated with inflammatory hyperalgesia. Na1.9 knockout (KO) mice, however, did not seem insensitive in conventional tests of acute nociception. Using electrophysiological, neurochemical, and behavioral techniques, we now show NaV1.9-null mice exhibit impaired mechanical and thermal sensory capacities and reduced electrical excitability of nociceptors. In single-fiber recordings from isolated skin, the electrical threshold of NaV1...
September 15, 2016: Pain
D Reiss, R A Ceredig, T Secher, J Boué, F Barreau, G Dietrich, C Gavériaux-Ruff
BACKGROUND: Opiates act through opioid receptors to diminish pain. Here, we investigated whether mu (MOR) and delta (DOR) receptor endogenous activity assessed in the whole mouse body or in particular at peripheral receptors on primary nociceptive neurons, control colonic pain. METHODS: We compared global MOR and DOR receptor knockout (KO) mice, mice with a conditional deletion of MOR and DOR in Nav1.8-positive nociceptive primary afferent neurons (cKO), and control floxed mice of both genders for visceral sensitivity...
October 17, 2016: European Journal of Pain: EJP
Xiao-Bo Wu, De-Li Cao, Xin Zhang, Bao-Chun Jiang, Lin-Xia Zhao, Bin Qian, Yong-Jing Gao
CXCL13 is a B lymphocyte chemoattractant and activates CXCR5 receptor in the immune system. Here we investigated whether CXCL13/CXCR5 mediates inflammatory pain in dorsal root ganglia (DRG) and the underlying mechanisms. Peripheral injection of complete Freund's Adjuvant (CFA) increased the expression of CXCL13 and CXCR5 in DRG neurons. In Cxcr5(-/-) mice, CFA-induced pain hypersensitivity were attenuated. Whole-cell patch-clamp recording showed that the excitability of dissociated DRG neurons was increased after CFA injection or CXCL13 incubation from wild-type (WT) mice, but not from Cxcr5(-/-) mice...
October 6, 2016: Scientific Reports
Qin Xu, Dakshesh Patel, Xian Zhang, Richard D Veenstra
Histone deacetylase (HDAC) inhibitors are small molecule anti-cancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage clamp experiments to measure cardiac sodium currents (INa) from wild-type neonatal mouse ventricular or human induced pluripotent stem cell derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228)...
September 16, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Hai-Li Pan, Ben-Long Liu, Wei Lin, Yu-Qiu Zhang
Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant sodium channel Nav1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA1 (also known as EDG2) and Nav1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in naïve rats and attenuated mechanical allodynia in a rat model of bone cancer...
October 2016: Neuroscience Bulletin
Andreas M Kist, Dagrun Sagafos, Anthony M Rush, Cristian Neacsu, Esther Eberhardt, Roland Schmidt, Lars Kristian Lunden, Kristin Ørstavik, Luisa Kaluza, Jannis Meents, Zhiping Zhang, Thomas Hedley Carr, Hugh Salter, David Malinowsky, Patrik Wollberg, Johannes Krupp, Inge Petter Kleggetveit, Martin Schmelz, Ellen Jørum, Angelika Lampert, Barbara Namer
Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations...
2016: PloS One
Guangyou Duan, Chongyang Han, Qingli Wang, Shanna Guo, Yuhao Zhang, Ying Ying, Penghao Huang, Li Zhang, Lawrence Macala, Palak Shah, Mi Zhang, Ningbo Li, Sulayman D Dib-Hajj, Stephen G Waxman, Xianwei Zhang
BACKGROUND: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. RESULTS: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity...
2016: Molecular Pain
Gang Chen, Rou-Gang Xie, Yong-Jing Gao, Zhen-Zhong Xu, Lin-Xia Zhao, Sangsu Bang, Temugin Berta, Chul-Kyu Park, Mark Lay, Wei Chen, Ru-Rong Ji
Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1...
August 19, 2016: Nature Communications
Mette R Rosberg, Susana Alvarez, Christian Krarup, Mihai Moldovan
Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/-, a model of CMT1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P0-/-, a CMT model with a much more severe neuropathy...
October 6, 2016: Neuroscience Letters
Brian S Tanaka, Peng Zhao, Fadia B Dib-Hajj, Valerie Morisset, Simon Tate, Stephen G Waxman, Sulayman D Dib-Hajj
Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain...
August 3, 2016: Molecular Medicine
Friederike Schlüter, Andreas Leffler
Voltage-gated Na(+) channels regulate neuronal excitability by generating the upstroke of action potentials. The α-subunits Nav1.7 and Nav1.8 are required for normal function of sensory neurons and thus for peripheral pain processing, but also for an increased excitability leading to an increased pain sensitivity under several conditions associated with oxidative stress. While little is known about the direct effects of oxidants on Nav1.7 and Nav1.8, a recent study on mouse dorsal root ganglion neurons suggested that oxidant-induced alterations of nociceptor excitability are primarily driven by Nav1...
October 1, 2016: Brain Research
M J Eberhardt, A Leffler
Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures...
July 11, 2016: Der Schmerz
Bianca T A de Greef, Ingemar S J Merkies, Margot Geerts, Catharina G Faber, Janneke G J Hoeijmakers
BACKGROUND: Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1...
2016: Trials
Wenhua Xu, Jun Zhang, Yuanyin Wang, Liecheng Wang, Xuxia Wang
Voltage-gated sodium channels (VGSCs), especially the tetrodotoxin-sensitive Nav1.3 and Nav1.7, and the tetrodotoxin-resistant Nav1.8 and Nav1.9, have been implicated in acute and chronic neuropathic pain. The aim of this study was to investigate the expression of VGSC Nav1.3, Nav1.7, Nav1.8, and Nav1.9 after nerve injury and their roles in the development of trigeminal neuralgia (TN). We used the infraorbital nerve-chronic constriction injury model of TN in the rat. The time course of changes in the mechanical pain threshold was examined...
August 17, 2016: Neuroreport
Xing-Jun Liu, Tong Liu, Gang Chen, Bing Wang, Xiao-Lu Yu, Cui Yin, Ru-Rong Ji
Increasing evidence suggests that neuro-immune and neuro-glial interactions are critically involved in chronic pain sensitization. It is well studied how immune/glial mediators sensitize pain, but how sensory neurons control neuroinflammation remains unclear. We employed Myd88 conditional knockout (CKO) mice, in which Myd88 was deleted in sodium channel subunit Nav1.8-expressing primary sensory neurons, to examine the unique role of neuronal MyD88 in regulating acute and chronic pain, and possible underlying mechanisms...
2016: Scientific Reports
Pierre-Eric Juif, Chiara Salio, Vivien Zell, Meggane Melchior, Adrien Lacaud, Nathalie Petit-Demouliere, Francesco Ferrini, Pascal Darbon, Ulrike Hanesch, Fernand Anton, Adalberto Merighi, Vincent Lelièvre, Pierrick Poisbeau
The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats...
August 2016: European Journal of Neuroscience
Hiroko Okuda, Atsuko Noguchi, Hatasu Kobayashi, Daiki Kondo, Kouji H Harada, Shohab Youssefian, Hirotomo Shioi, Risako Kabata, Yuki Domon, Kazufumi Kubota, Yutaka Kitano, Yasunori Takayama, Toshiaki Hitomi, Kousaku Ohno, Yoshiaki Saito, Takeshi Asano, Makoto Tominaga, Tsutomu Takahashi, Akio Koizumi
Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence...
2016: PloS One
Mette R Rosberg, Susana Alvarez, Dennis Klein, Finn Cilius Nielsen, Rudolf Martini, S Rock Levinson, Christian Krarup, Mihai Moldovan
Mice heterozygously deficient for the myelin protein P0 gene (P0+/-) develop a slowly progressing neuropathy modeling demyelinating Charcot-Marie-Tooth disease (CMT1B). The aim of the study was to investigate the long-term progression of motor dysfunction in P0+/- mice at 3, 7, 12 and 20months. By comparison with WT littermates, P0+/- showed a decreasing motor performance with age. This was associated with a progressive reduction in amplitude and increase in latency of the plantar compound muscle action potential (CMAP) evoked by stimulation of the tibial nerve at ankle...
September 2016: Neurobiology of Disease
M Kocmalova, M Joskova, S Franova, P Banovcin, M Sutovska
Expression of voltage-gated sodium channels (Nav) takes place in the airways and the role of Nav1.7 and Nav1.8 in the control of airway's defense reflexes has been confirmed. The activation of Nav channels is crucial for cough initiation and airway smooth muscle reactivity, but it is unknown whether these channels regulate ciliary beating. This study evaluated the involvement of Nav1.7 and Nav1.8 channels in the airway defense mechanisms using their pharmacological blockers in healthy guinea pigs and in the experimental allergic asthma model...
2016: Advances in Experimental Medicine and Biology
Zhen Liu, Fei Wang, Gregory Fischer, Quinn H Hogan, Hongwei Yu
BACKGROUND: Gαi-interacting protein (GINIP) is expressed specifically in dorsal root ganglion (DRG) neurons and functions in modulation of peripheral gamma-aminobutyric acid B receptor (GBR). Genetic deletion of GINIP leads to impaired responsiveness to GBR agonist-mediated analgesia in rodent. It is, however, not defined whether nerve injury changes GINIP expression. RESULTS: Immunolabeling with validated antibody revealed GINIP expression in ~40% of total lumbar DRG neurons in normal adult rats...
2016: Molecular Pain
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