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      Hunting for origins of migraine pain: cluster analysis of spontaneous and capsaicin-induced firing in meningeal trigeminal nerve fibers

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          Abstract

          Trigeminal nerves in meninges are implicated in generation of nociceptive firing underlying migraine pain. However, the neurochemical mechanisms of nociceptive firing in meningeal trigeminal nerves are little understood. In this study, using suction electrode recordings from peripheral branches of the trigeminal nerve in isolated rat meninges, we analyzed spontaneous and capsaicin-induced orthodromic spiking activity. In control, biphasic single spikes with variable amplitude and shapes were observed. Application of the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin to meninges dramatically increased firing whereas the amplitudes and shapes of spikes remained essentially unchanged. This effect was antagonized by the specific TRPV1 antagonist capsazepine. Using the clustering approach, several groups of uniform spikes (clusters) were identified. The clustering approach combined with capsaicin application allowed us to detect and to distinguish “responder” (65%) from “non-responder” clusters (35%). Notably, responders fired spikes at frequencies exceeding 10 Hz, high enough to provide postsynaptic temporal summation of excitation at brainstem and spinal cord level. Almost all spikes were suppressed by tetrodotoxin (TTX) suggesting an involvement of the TTX-sensitive sodium channels in nociceptive signaling at the peripheral branches of trigeminal neurons. Our analysis also identified transient (desensitizing) and long-lasting (slowly desensitizing) responses to the continuous application of capsaicin. Thus, the persistent activation of nociceptors in capsaicin-sensitive nerve fibers shown here may be involved in trigeminal pain signaling and plasticity along with the release of migraine-related neuropeptides from TRPV1 positive neurons. Furthermore, cluster analysis could be widely used to characterize the temporal and neurochemical profiles of other pain transducers likely implicated in migraine.

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          Most cited references39

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          Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain.

          The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain. Copyright © 2014 Elsevier Inc. All rights reserved.
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            High-dimensional cluster analysis with the masked EM algorithm.

            Cluster analysis faces two problems in high dimensions: the "curse of dimensionality" that can lead to overfitting and poor generalization performance and the sheer time taken for conventional algorithms to process large amounts of high-dimensional data. We describe a solution to these problems, designed for the application of spike sorting for next-generation, high-channel-count neural probes. In this problem, only a small subset of features provides information about the cluster membership of any one data vector, but this informative feature subset is not the same for all data points, rendering classical feature selection ineffective. We introduce a "masked EM" algorithm that allows accurate and time-efficient clustering of up to millions of points in thousands of dimensions. We demonstrate its applicability to synthetic data and to real-world high-channel-count spike sorting data.
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              Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

              The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                28 July 2015
                2015
                : 9
                : 287
                Affiliations
                [1] 1Laboratory of Neurobiology, Kazan Federal University Kazan, Russia
                [2] 2Department of Physiology, Kazan State Medical University Kazan, Russia
                [3] 3Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland Kuopio, Finland
                [4] 4Medical Faculty, Department of Physiology, Abant Izzet Baysal University Bolu, Turkey
                [5] 5Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS Moscow, Russia
                [6] 6Kazan Institute of Biochemistry and Biophysics Kazan, Russia
                [7] 7INSERM U901/Aix Marseille University Marseille, France
                Author notes

                Edited by: Enrico Cherubini, International School for Advanced Studies, Italy

                Reviewed by: Anna Andreou, Imperial College London, UK; Marilena Griguoli, European Research Brain Institute, Italy

                *Correspondence: R. Giniatullin, Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627/Neulaniementie 2, 70211 Kuopio, Finland rashid.giniatullin@ 123456uef.fi
                Article
                10.3389/fncel.2015.00287
                4516892
                25667569
                ef4aac04-bf3c-4eb6-bc94-92b6c6fb5864
                Copyright © 2015 Zakharov, Vitale, Kilinc, Koroleva, Fayuk, Shelukhina, Naumenko, Skorinkin, Khazipov and Giniatullin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 April 2015
                : 13 July 2015
                Page count
                Figures: 9, Tables: 1, Equations: 0, References: 46, Pages: 14, Words: 8804
                Funding
                Funded by: Kazan Federal University
                Funded by: Government of the Russian Federation
                Award ID: grant No.11.G34.31.0075
                Funded by: Finnish Academy
                Award ID: grant 277442
                Funded by: Russian Scientific Fund
                Award ID: Grant No.14-15-00618
                Funded by: Russian Foundation for Basic Research
                Categories
                Neuroscience
                Original Research

                Neurosciences
                pain,trigeminal nerve,spike,capsaicin,cluster analysis
                Neurosciences
                pain, trigeminal nerve, spike, capsaicin, cluster analysis

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