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Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice.

Publication ,  Journal Article
Berta, T; Liu, Y-C; Xu, Z-Z; Ji, R-R
Published in: Neuroscience
September 5, 2013

Accumulating evidence indicates that activation of spinal cord astrocytes contributes importantly to nerve injury and inflammation-induced persistent pain and chronic opioid-induced antinociceptive tolerance. Phosphorylation of extracellular signal-regulated kinase (pERK) and induction of interleukin-1 beta (IL-1β) in spinal astrocytes have been implicated in astrocytes-mediated pain. Tissue plasminogen activator (tPA) is a serine protease that has been extensively used to treat stroke. We examined the potential involvement of tPA in chronic opioid-induced antinociceptive tolerance and activation of spinal astrocytes using tPA knockout (tPA(-/-)) mice and astrocyte cultures. tPA(-/-) mice exhibited unaltered nociceptive pain and morphine-induced acute analgesia. However, the antinociceptive tolerance, induced by chronic morphine (10mg/kg/day, s.c.), is abrogated in tPA(-/-) mice. Chronic morphine induces tPA expression in glial fibrillary acidic protein (GFAP)-expressing spinal cord astrocytes. Chronic morphine also increases IL-1β expression in GFAP-expressing astrocytes, which is abolished in tPA-deficient mice. In cultured astrocytes, morphine treatment increases tPA, IL-1β, and pERK expression, and the increased IL-1β and pERK expression is abolished in tPA-deficient astrocytes. tPA is also sufficient to induce IL-1β and pERK expression in astrocyte cultures. Intrathecal injection of tPA results in up-regulation of GFAP and pERK in spinal astrocytes but not up-regulation of ionized calcium binding adapter molecule 1 in spinal microglia. Finally, intrathecal tPA elicits persistent mechanical allodynia, which is inhibited by the astroglial toxin alpha-amino adipate and the MEK (ERK kinase) inhibitor U0126. Collectively, these data suggest an important role of tPA in regulating astrocytic signaling, pain hypersensitivity, and morphine tolerance.

Duke Scholars

Published In

Neuroscience

DOI

EISSN

1873-7544

Publication Date

September 5, 2013

Volume

247

Start / End Page

376 / 385

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Spinal Cord
  • Signal Transduction
  • Phosphorylation
  • Neurology & Neurosurgery
  • Morphine
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Berta, T., Liu, Y.-C., Xu, Z.-Z., & Ji, R.-R. (2013). Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience, 247, 376–385. https://doi.org/10.1016/j.neuroscience.2013.05.018
Berta, T., Y. -. C. Liu, Z. -. Z. Xu, and R. -. R. Ji. “Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice.Neuroscience 247 (September 5, 2013): 376–85. https://doi.org/10.1016/j.neuroscience.2013.05.018.
Berta, T., et al. “Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice.Neuroscience, vol. 247, Sept. 2013, pp. 376–85. Pubmed, doi:10.1016/j.neuroscience.2013.05.018.
Journal cover image

Published In

Neuroscience

DOI

EISSN

1873-7544

Publication Date

September 5, 2013

Volume

247

Start / End Page

376 / 385

Location

United States

Related Subject Headings

  • Tissue Plasminogen Activator
  • Spinal Cord
  • Signal Transduction
  • Phosphorylation
  • Neurology & Neurosurgery
  • Morphine
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male