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Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.

dc.contributor.author Caron, MG
dc.contributor.author Chavkin, C
dc.contributor.author Czyzyk, TA
dc.contributor.author Lefkowitz, Robert J
dc.contributor.author McLaughlin, JP
dc.contributor.author Petraschka, M
dc.contributor.author Pintar, JE
dc.contributor.author Terman, GW
dc.contributor.author Westenbroek, RE
dc.contributor.author Xu, M
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.uri https://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.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.issue 19
duke.description.volume 24
dc.relation.journal Journal of Neuroscience
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/15140929
pubs.begin-page 4576
pubs.end-page 4584
pubs.issue 19
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biochemistry
pubs.organisational-group Cell Biology
pubs.organisational-group Chemistry
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Neurobiology
pubs.organisational-group Pathology
pubs.organisational-group School of Medicine
pubs.organisational-group Trinity College of Arts & Sciences
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 24
dc.identifier.eissn 1529-2401


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