Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms

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dc.contributor.authorGriggs, R.B.
dc.contributor.authorDonahue, R.R.
dc.contributor.authorMorgenweck, J.
dc.contributor.authorGrace, P.M.
dc.contributor.authorSutton, A.
dc.contributor.authorWatkins, L.R.
dc.contributor.authorTaylor, B.K.
dc.date.issued2015
dc.description.abstractRepeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal (i.t.) injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid antihyperalgesic actions of PPARγ activation, we administered pioglitazone to rats with spared nerve injury and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 minutes of injection, consistent with a nongenomic mechanism. Systemic or i.t. administration of GW9662, a PPARγ antagonist, inhibited the antihyperalgesic actions of intraperitoneal or i.t. pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of nongenomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When coadministered intrathecally, anisomycin did not change pioglitazone antihyperalgesia at an early 7.5-minute time point, further supporting a rapid nongenomic mechanism. At later time points, anisomycin reduced pioglitazone antihyperalgesia, suggesting delayed recruitment of genomic mechanisms. Pioglitazone reduction of spared nerve injury-induced increases in GFAP expression occurred more rapidly than expected, within 60 minutes. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent of canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation and through both genomic and nongenomic PPARγ mechanisms.
dc.description.statementofresponsibilityRyan B. Griggs, Renee R. Donahue, Jenny Morgenweck, Peter M. Grace, Amanda Sutton, Linda R. Watkins, Bradley K. Taylor
dc.identifier.citationPain, 2015; 156(3):469-482
dc.identifier.doi10.1097/01.j.pain.0000460333.79127.be
dc.identifier.issn0304-3959
dc.identifier.issn1872-6623
dc.identifier.orcidGrace, P.M. [0000-0002-8999-1220]
dc.identifier.urihttps://hdl.handle.net/2440/134136
dc.language.isoen
dc.publisherInternational Association for the Study of Pain; Ovid
dc.relation.grant5R01 N5062306
dc.relation.grantR01NS045954
dc.relation.grantT32NS077889
dc.relation.grantF31NS083292
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1054091
dc.rights© 2015 the International Association for the Study of Pain
dc.source.urihttps://doi.org/10.1097/01.j.pain.0000460333.79127.be
dc.subjectNeuropathic; pain; PPAR gamma; astrocyte; pioglitazone; nongenomic
dc.subject.meshAstrocytes
dc.subject.meshAnimals
dc.subject.meshRats
dc.subject.meshRats, Sprague-Dawley
dc.subject.meshNeuralgia
dc.subject.meshHyperalgesia
dc.subject.meshAnimal Diseases
dc.subject.meshCapsaicin
dc.subject.meshThiazolidinediones
dc.subject.meshGlial Fibrillary Acidic Protein
dc.subject.meshOncogene Proteins v-fos
dc.subject.meshPPAR gamma
dc.subject.meshHypoglycemic Agents
dc.subject.meshInjections, Intraventricular
dc.subject.meshAnalysis of Variance
dc.subject.meshArea Under Curve
dc.subject.meshPain Threshold
dc.subject.meshPsychomotor Performance
dc.subject.meshMale
dc.subject.meshNociception
dc.subject.meshSpinal Cord Dorsal Horn
dc.subject.meshPioglitazone
dc.titlePioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms
dc.title.alternativePioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARgamma mechanisms
dc.typeJournal article
pubs.publication-statusPublished

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