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dc.contributor.author Xu, M
dc.contributor.author Petraschka, M
dc.contributor.author McLaughlin, JP
dc.contributor.author Westenbroek, RE
dc.contributor.author Caron, MG
dc.contributor.author Lefkowitz, RJ
dc.contributor.author Czyzyk, TA
dc.contributor.author Pintar, JE
dc.contributor.author Terman, GW
dc.contributor.author Chavkin, C
dc.coverage.spatial United States
dc.date.accessioned 2012-10-24T20:24:35Z
dc.date.issued 2004-05-12
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/15140929
dc.identifier 24/19/4576
dc.identifier.citation J Neurosci, 2004, 24 (19), pp. 4576 - 4584
dc.identifier.uri http://hdl.handle.net/10161/5936
dc.description.abstract Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.
dc.format.extent 4576 - 4584
dc.language eng
dc.relation.ispartof J Neurosci
dc.relation.isversionof 10.1523/JNEUROSCI.5552-03.2004
dc.subject Animals
dc.subject Astrocytes
dc.subject Disease Models, Animal
dc.subject Disease Progression
dc.subject Drug Tolerance
dc.subject Dynorphins
dc.subject Enkephalins
dc.subject G-Protein-Coupled Receptor Kinase 3
dc.subject Hyperalgesia
dc.subject Lumbosacral Region
dc.subject Mice
dc.subject Mice, Inbred C57BL
dc.subject Mice, Knockout
dc.subject Narcotic Antagonists
dc.subject Narcotics
dc.subject Neuralgia
dc.subject Neurons
dc.subject Protein Precursors
dc.subject Protein-Serine-Threonine Kinases
dc.subject Receptors, Opioid
dc.subject Receptors, Opioid, kappa
dc.subject Sciatic Neuropathy
dc.subject Spinal Cord
dc.title Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.
dc.type Journal Article
duke.description.endpage 4584 en_US
duke.description.issue 19 en_US
duke.description.startpage 4576 en_US
duke.description.volume 24 en_US
dc.relation.journal Journal of Neuroscience en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/15140929
pubs.issue 19
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Institutes and Provost's Academic Units
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers/Duke Institute for Brain Sciences
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Cell Biology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Neurobiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Cardiology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/Trinity College of Arts & Sciences
pubs.organisational-group /Duke/Trinity College of Arts & Sciences/Chemistry
pubs.publication-status Published
pubs.volume 24
dc.identifier.eissn 1529-2401

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