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

Publication ,  Journal Article
Xu, M; Petraschka, M; McLaughlin, JP; Westenbroek, RE; Caron, MG; Lefkowitz, RJ; Czyzyk, TA; Pintar, JE; Terman, GW; Chavkin, C
Published in: J Neurosci
May 12, 2004

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.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

May 12, 2004

Volume

24

Issue

19

Start / End Page

4576 / 4584

Location

United States

Related Subject Headings

  • Spinal Cord
  • Sciatic Neuropathy
  • Receptors, Opioid, kappa
  • Receptors, Opioid
  • Protein Serine-Threonine Kinases
  • Protein Precursors
  • Neurons
  • Neurology & Neurosurgery
  • Neuralgia
  • Narcotics
 

Citation

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Xu, M., Petraschka, M., McLaughlin, J. P., Westenbroek, R. E., Caron, M. G., Lefkowitz, R. J., … Chavkin, C. (2004). Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci, 24(19), 4576–4584. https://doi.org/10.1523/JNEUROSCI.5552-03.2004
Xu, Mei, Michael Petraschka, Jay P. McLaughlin, Ruth E. Westenbroek, Marc G. Caron, Robert J. Lefkowitz, Traci A. Czyzyk, John E. Pintar, Gregory W. Terman, and Charles Chavkin. “Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.J Neurosci 24, no. 19 (May 12, 2004): 4576–84. https://doi.org/10.1523/JNEUROSCI.5552-03.2004.
Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, et al. Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci. 2004 May 12;24(19):4576–84.
Xu, Mei, et al. “Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.J Neurosci, vol. 24, no. 19, May 2004, pp. 4576–84. Pubmed, doi:10.1523/JNEUROSCI.5552-03.2004.
Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Terman GW, Chavkin C. Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. J Neurosci. 2004 May 12;24(19):4576–4584.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

May 12, 2004

Volume

24

Issue

19

Start / End Page

4576 / 4584

Location

United States

Related Subject Headings

  • Spinal Cord
  • Sciatic Neuropathy
  • Receptors, Opioid, kappa
  • Receptors, Opioid
  • Protein Serine-Threonine Kinases
  • Protein Precursors
  • Neurons
  • Neurology & Neurosurgery
  • Neuralgia
  • Narcotics