In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model

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• dc.contributor.author Hipótilo, Lucia
• dc.contributor.author Fakira, Amanda K.
• dc.contributor.author Cabañero Ferri, David
• dc.contributor.author Blandón, Rebecca
• dc.contributor.author Carlton, Susan M.
• dc.contributor.author Morón, Jose A.
• dc.contributor.author Melyan, Zara
• dc.date.accessioned 2019-06-20T09:34:55Z
• dc.date.available 2019-06-20T09:34:55Z
• dc.date.issued 2015
• dc.description.abstract N-methyl-D-aspartate receptor (NMDAR) antagonists have been shown to reduce mechanical hypersensitivity in animal models of inflammatory pain. However, their clinical use is associated with significant dose-limiting side effects. Small-conductance Ca-activated K channels (SK) have been shown to modulate NMDAR activity in the brain. We demonstrate that in vivo activation of SK channels in the spinal cord can alleviate mechanical hypersensitivity in a rat model of inflammatory pain. Intrathecal (i.t.) administration of the SK channel activator, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), attenuates complete Freund adjuvant (CFA)-induced mechanical hypersensitivity in a dose-dependent manner. Postsynaptic expression of the SK channel subunit, SK3, and apamin-sensitive SK channel-mediated currents recorded from superficial laminae are significantly reduced in the dorsal horn (DH) after CFA. Complete Freund adjuvant-induced decrease in SK-mediated currents can be reversed in vitro by bath application of NS309. In addition, immunostaining for the SK3 subunit indicates that SK3-containing channels within DH neurons can have both somatic and dendritic localization. Double immunostaining shows coexpression of SK3 and NMDAR subunit, NR1, compatible with functional interaction. Moreover, we demonstrate that i.t. coadministration of NS309 with an NMDAR antagonist reduces the dose of NMDAR antagonist, DL-2-amino-5-phosphonopentanoic acid (DL-AP5), required to produce antinociceptive effects in the CFA model. This reduction could attenuate the unwanted side effects associated with NMDAR antagonists, giving this combination potential clinical implications.
• dc.description.sponsorship This work was supported by NIH, NIDA grants DA027460 (JAM) and by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1 RR024156
• dc.format.mimetype application/pdf
• dc.identifier.citation Hipólito L, Fakira AK, Cabañero D, Blandón R, Carlton SM, Morón JA et al. In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model. Pain. 2015 May;156(5):849-58. DOI: 10.1097/j.pain.0000000000000124
• dc.identifier.doi http://dx.doi.org/10.1097/j.pain.0000000000000124
• dc.identifier.issn 0304-3959
• dc.identifier.uri http://hdl.handle.net/10230/41854
• dc.language.iso eng
• dc.publisher Lippincott Williams & Wilkins
• dc.relation.ispartof Pain. 2015 May;156(5):849-58
• dc.rights © Lippincott Williams & Wilkins "This is a non-final version of an article published in final form in Hipólito L, Fakira AK, Cabañero D, Blandón R, Carlton SM, Morón JA et al. In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model. Pain. 2015 May; 156(5): 849-58. http://dx.doi.org/10.1097/j.pain.0000000000000124
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Indole
• dc.subject.other Inflammation
• dc.subject.other Oxima
• dc.subject.other Dolor -- Tractament
• dc.subject.other Medul·la espinal
• dc.title In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion