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

Abstract

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.

• Authors: Folabomi A Oladosu, Matthew S Conrad, Sandra C O'Buckley, Naim U Rashid, Gary D Slade, Andrea G Nackley
• Journal: PloS one (PLoS One) Vol. 10 Issue 8 Pg. e0135711 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26270813 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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