RAPID REPORT: An<i>in vivo</i>tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors

Stürzebecher, Annika; Hu, Jing; Smith, Ewan St. John; Frahm, Silke; Santos-Torres, Julio; Kampfrath, Branka; Auer, Sebastian; Lewin, Gary R.; Ibañez–Tallon, Inés

doi:10.1113/jphysiol.2010.187112

Cited by 30 publications

(34 citation statements)

References 34 publications

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“…Recordings from single units were made as previously described 52,53 , however, we applied cooling stimuli (Peltier device) with almost identical amplitudes and kinetics to those employed in behavioral training paradigms and cortical recordings. Two cooling ramps were routinely applied, 32-22 ˚C to probe for low-threshold units and a second 32-12 ˚C stimulus to characterize high-threshold responders and suprathreshold firing of coldsensitive fibers.…”

Section: Skin-nerve Preparation and Sensory Afferent Recordingsmentioning

confidence: 99%

A somatosensory circuit for cooling perception in mice

et al. 2014

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The temperature of an object provides important somatosensory information for animals performing tactile tasks. Humans can perceive skin cooling of less than one degree, but the sensory afferents and central circuits they engage to enable the perception of surface temperature are poorly understood. To address these questions, we examined the perception of glabrous skin cooling in mice. We found that mice were also capable of perceiving small amplitude skin cooling and that primary somatosensory (S1) cortical neurons were required for cooling perception. Moreover, the absence of the menthol-gated transient receptor potential melastatin 8 ion channel in sensory afferent fibers eliminated the ability to perceive cold and the corresponding activation of S1 neurons. Our results identify parts of a neural circuit underlying cold perception in mice and provide a new model system for the analysis of thermal processing and perception and multimodal integration.An accurate sense of surface temperature helps animals to perceive object structure and identity. Psychophysical experiments have shown that humans are able to perceive tiny changes in skin cooling with a range between 0.4 and 1.8 ˚C 1,2 . It has, however, proved challenging to assess the perceptual ability of rodents to discriminate small temperature steps at threshold levels.Classical paw withdrawal tests cannot differentiate between reflexive avoidance behavior and sensory perception 3 . Two-plate thermal preference arenas have shown that mice avoid cooler floor temperatures [4][5][6] , but this test has limited spatial and temporal control of the stimulus and lacks fine-grained resolution for near threshold perception. We therefore developed a shortlatency, goal-directed thermal perception task using the glabrous skin of the mouse forepaw.A general dogma is that all somatosensory input, including thermal, is integrated by the primary somatosensory cortex (S1) to form a coherent sensory percept. S1 is necessary for tactile somatosensory perception in rodents [7][8][9][10][11][12][13] . The role of S1 in thermal perception, however, is under debate, 3 with three studies concluding that rodent S1 is not involved [14][15][16] and another concluding that it is 17 . This may be because these studies used large cortical lesions with long recovery and retraining periods in freely moving rats that used facial regions to detect temperature [14][15][16][17] .Likewise, very little is known about the underlying cortical neural processing of non-noxious thermal stimuli in rodents. To the best of our knowledge, only one study, conducted in anesthetized rats stimulating scrotal skin, has shown extracellular responses of cortical neurons to thermal stimulation 18 . At the sensory periphery, a range of primary afferents including myelinated Aβ mechanoreceptors 2,19 , thinly myelinated Aδ-fibers and unmyelinated polymodal C fibers, fire during skin cooling 4,20,21 . Although it is thought that thickly myelinated Aδ fibers are responsible for cooling perception, C fibers ...

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Section: Skin-nerve Preparation and Sensory Afferent Recordingsmentioning

confidence: 99%

A somatosensory circuit for cooling perception in mice

et al. 2014

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“…However gene deletion of Nav1.8 leads to increased Nav1.7 channels and TTX-sensitive currents in nociceptors of Nav1.8 knockout mice [19] making it difficult to interpret the single contribution of each channel type to pain modalities (inflammatory, neuropathic acute pain or cold pain). To address this, we genetically delivered t-MrVIa μO-conotoxin (preferential blocker of Na v 1.8) to nociceptors by mouse BAC transgenesis [12]. Electrophysiological analyses showed that the t-toxin inhibited TTX-R Na + currents at the membrane, as it was released by enzymatic cleavage of the GPI anchor [12].…”

Section: Application Of T-toxins To the Dissection Of Mammalian Circuitsmentioning

confidence: 99%

“…To address this, we genetically delivered t-MrVIa μO-conotoxin (preferential blocker of Na v 1.8) to nociceptors by mouse BAC transgenesis [12]. Electrophysiological analyses showed that the t-toxin inhibited TTX-R Na + currents at the membrane, as it was released by enzymatic cleavage of the GPI anchor [12]. Behaviorally, t-toxin transgenic mice displayed reduced inflammatory and cold pain perception [12].…”

Section: Application Of T-toxins To the Dissection Of Mammalian Circuitsmentioning

confidence: 99%

“…Electrophysiological analyses showed that the t-toxin inhibited TTX-R Na + currents at the membrane, as it was released by enzymatic cleavage of the GPI anchor [12]. Behaviorally, t-toxin transgenic mice displayed reduced inflammatory and cold pain perception [12]. As research on venom peptide toxins progresses, it would be interesting to identify and test other antagonists of Na v channels expressed in central neurons for cell-specific silencing studies in the brain.…”

Section: Application Of T-toxins To the Dissection Of Mammalian Circuitsmentioning

confidence: 99%

“…Thus besides mouse BAC transgenesis, and constitutive viral vectors [9,12] (Figure 1), these genetic tools are now being used in intersectional strategies that employ Cre driver mouse lines and Cre-dependent viral vectors to assess the contributions of specific cell types to specific behaviors by manipulation of neuronal activity within specific cell populations in the living mouse.…”

Section: Application Of T-toxins To the Dissection Of Mammalian Circuitsmentioning

confidence: 99%

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Tethering toxins and peptide ligands for modulation of neuronal function

Ibañez–Tallon

Nitabach

2012

Current Opinion in Neurobiology

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Tethering genetically encoded peptide toxins or ligands close to their point of activity at the cell plasma membrane provides a new approach to the study of cell networks and neuronal circuits, as it allows selective targeting of specific cell populations, enhances the working concentration of the ligand or blocker peptide, and permits the engineering of a large variety of t-peptides (e.g., including use of fluorescent markers, viral vectors and point mutation variants). This review describes the development of tethered toxins and peptides derived from the identification of the cell surface nAChR modulator lynx1, the existence of related endogenous cell surface modulators of nAChR and AMPA receptors, and the application of the t-toxin and t-neuropeptide technology to the dissection of neuronal circuits in metazoans.

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Specific paucity of unmyelinated C‐fibers in cutaneous peripheral nerves of the African naked‐mole rat: Comparative analysis using six species of bathyergidae

Smith

Purfürst

Grigoryan

et al. 2012

J of Comparative Neurology

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In mammalian peripheral nerves, unmyelinated C-fibers usually outnumber myelinated A-fibers. By using transmission electron microscopy, we recently showed that the saphenous nerve of the naked mole-rat (Heterocephalus glaber) has a C-fiber deficit manifested as a substantially lower C:A-fiber ratio compared with other mammals. Here we determined the uniqueness of this C-fiber deficit by performing a quantitative anatomical analysis of several peripheral nerves in five further members of the Bathyergidae mole-rat family: silvery (Heliophobius argenteocinereus), giant (Fukomys mechowii), Damaraland (Fukomys damarensis), Mashona (Fukomys darlingi), and Natal (Cryptomys hottentotus natalensis) mole-rats. In the largely cutaneous saphenous and sural nerves, the naked mole-rat had the lowest C:A-fiber ratio (∼1.5:1 compared with ∼3:1), whereas, in nerves innervating both skin and muscle (common peroneal and tibial) or just muscle (lateral/medial gastrocnemius), this pattern was mostly absent. We asked whether lack of hair follicles alone accounts for the C-fiber paucity by using as a model a mouse that loses virtually all its hair as a consequence of conditional deletion of the β-catenin gene in the skin. These β-catenin loss-of function mice (β-cat LOF mice) displayed only a mild decrease in C:A-fiber ratio compared with wild-type mice (4.42 compared with 3.81). We suggest that the selective cutaneous C-fiber deficit in the cutaneous nerves of naked mole-rats is unlikely to be due primarily to lack of skin hair follicles. Possible mechanisms contributing to this unique peripheral nerve anatomy are discussed. J. Comp. Neurol. 520:2785–2803, 2012. © 2012 Wiley Periodicals, Inc.

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RAPID REPORT: Anin vivotethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors

Cited by 30 publications

References 34 publications

A somatosensory circuit for cooling perception in mice

A somatosensory circuit for cooling perception in mice

Tethering toxins and peptide ligands for modulation of neuronal function

Specific paucity of unmyelinated C‐fibers in cutaneous peripheral nerves of the African naked‐mole rat: Comparative analysis using six species of bathyergidae

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