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Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.

Publication ,  Journal Article
Oladosu, FA; Conrad, MS; O'Buckley, SC; Rashid, NU; Slade, GD; Nackley, AG
Published in: PLoS One
2015

BACKGROUND: A subset of the population receiving opioids for the treatment of acute and chronic clinical pain develops a paradoxical increase in pain sensitivity known as opioid-induced hyperalgesia. Given that opioid analgesics are one of few treatments available against clinical pain, it is critical to determine the key molecular mechanisms that drive opioid-induced hyperalgesia in order to reduce its prevalence. Recent evidence implicates a splice variant of the mu opioid receptor known as MOR-1K in the emergence of opioid-induced hyperalgesia. Results from human genetic association and cell signaling studies demonstrate that MOR-1K contributes to decreased opioid analgesic responses and produces increased cellular activity via Gs signaling. Here, we conducted the first study to directly test the role of MOR-1K in opioid-induced hyperalgesia. METHODS AND RESULTS: In order to examine the role of MOR-1K in opioid-induced hyperalgesia, we first assessed pain responses to mechanical and thermal stimuli prior to, during, and following chronic morphine administration. Results show that genetically diverse mouse strains (C57BL/6J, 129S6, and CXB7/ByJ) exhibited different morphine response profiles with corresponding changes in MOR-1K gene expression patterns. The 129S6 mice exhibited an analgesic response correlating to a measured decrease in MOR-1K gene expression levels, while CXB7/ByJ mice exhibited a hyperalgesic response correlating to a measured increase in MOR-1K gene expression levels. Furthermore, knockdown of MOR-1K in CXB7/ByJ mice via chronic intrathecal siRNA administration not only prevented the development of opioid-induced hyperalgesia, but also unmasked morphine analgesia. CONCLUSIONS: These findings suggest that MOR-1K is likely a necessary contributor to the development of opioid-induced hyperalgesia. With further research, MOR-1K could be exploited as a target for antagonists that reduce or prevent opioid-induced hyperalgesia.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

8

Start / End Page

e0135711

Location

United States

Related Subject Headings

  • Receptors, Opioid, mu
  • Morphine
  • Mice
  • Male
  • Hyperalgesia
  • Humans
  • Genetic Variation
  • General Science & Technology
  • Gene Expression Regulation
  • Female
 

Citation

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ICMJE
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Oladosu, F. A., Conrad, M. S., O’Buckley, S. C., Rashid, N. U., Slade, G. D., & Nackley, A. G. (2015). Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. PLoS One, 10(8), e0135711. https://doi.org/10.1371/journal.pone.0135711
Oladosu, Folabomi A., Matthew S. Conrad, Sandra C. O’Buckley, Naim U. Rashid, Gary D. Slade, and Andrea G. Nackley. “Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.PLoS One 10, no. 8 (2015): e0135711. https://doi.org/10.1371/journal.pone.0135711.
Oladosu FA, Conrad MS, O’Buckley SC, Rashid NU, Slade GD, Nackley AG. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. PLoS One. 2015;10(8):e0135711.
Oladosu, Folabomi A., et al. “Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia.PLoS One, vol. 10, no. 8, 2015, p. e0135711. Pubmed, doi:10.1371/journal.pone.0135711.
Oladosu FA, Conrad MS, O’Buckley SC, Rashid NU, Slade GD, Nackley AG. Mu Opioid Splice Variant MOR-1K Contributes to the Development of Opioid-Induced Hyperalgesia. PLoS One. 2015;10(8):e0135711.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

8

Start / End Page

e0135711

Location

United States

Related Subject Headings

  • Receptors, Opioid, mu
  • Morphine
  • Mice
  • Male
  • Hyperalgesia
  • Humans
  • Genetic Variation
  • General Science & Technology
  • Gene Expression Regulation
  • Female