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The Journal of Neuroscience, May 12, 2004, 24(19):4576-4584; doi:10.1523/JNEUROSCI.5552-03.2004

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Development/Plasticity/Repair
Neuropathic Pain Activates the Endogenous Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance

Mei Xu,^1 * Michael Petraschka,^1 * Jay P. McLaughlin,¹ Ruth E. Westenbroek,¹ Marc G. Caron,³ Robert J. Lefkowitz,⁴ Traci A. Czyzyk,⁵ John E. Pintar,⁵ Gregory W. Terman,² and Charles Chavkin¹

Departments of ¹Pharmacology and ²Anesthesiology, University of Washington School of Medicine, Seattle, Washington 98195, Departments of ³Cell Biology and ⁴Biochemistry and Medicine, Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, North Carolina 27710, and ⁵Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

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 [ 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 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.

Key words: opioid receptor; opiate; dynorphin; receptor phosphorylation; desensitization; allodynia; hyperalgesia

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Received Dec 17, 2003; revised February 12, 2004; accepted April 6, 2004.

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