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

PLoS One. 2015 Aug 13;10(8):e0135711. doi: 10.1371/journal.pone.0135711. eCollection 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing*
  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology
  • Animals
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Genetic Variation
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / genetics*
  • Male
  • Mice
  • Morphine / administration & dosage*
  • Morphine / adverse effects
  • Morphine / pharmacology
  • Receptors, Opioid, mu / genetics*


  • Analgesics, Opioid
  • Oprm protein, mouse
  • Receptors, Opioid, mu
  • Morphine