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dc.contributor.authorTsantoulas, Christoforosen
dc.contributor.authorZhu, Lanen
dc.contributor.authorYip, Pingen
dc.contributor.authorGrist, Johnen
dc.contributor.authorMichael, Gregory J.en
dc.contributor.authorMcMahon, Stephen B.en
dc.date.accessioned2015-04-30T13:44:20Z
dc.date.available2015-04-30T13:44:20Z
dc.date.issued2014-02-19
dc.identifier.citationTsantoulas, C., Zhu, L., Yip, P. et al. (2014) Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input. Experimental neurology, 251, pp. 115-126en
dc.identifier.issn1090-2430
dc.identifier.urihttp://hdl.handle.net/2086/10926
dc.descriptionThis article is available on the publishers website via Open Accessen
dc.description.abstractPeripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naive neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states.en
dc.language.isoenen
dc.publisherExperimental neurologyen
dc.subjectperipheral nerve injuryen
dc.subjectneuropathic painen
dc.subjectraten
dc.subjectvoltage gated potassium channelen
dc.subjectKv2en
dc.subjectintracelullar recordingen
dc.subjectelectrophysiologyen
dc.subjectdorsal root ganglionen
dc.titleKv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.en
dc.typeArticleen
dc.identifier.doihttp://dx.doi.org/10.1016/j.expneurol.2013.11.011
dc.peerreviewedYesen
dc.funderWellcome Trust-funded London Pain Consortiumen
dc.funderEPSRC (Engineering and Physical Sciences Research Council)en
dc.projectidRG53462en
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en


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