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

• Published in: PloS one 2015-08, Vol.10 (8), p.e0135711
• Main Authors: Oladosu, Folabomi A, Conrad, Matthew S, O'Buckley, Sandra C, Rashid, Naim U, Slade, Gary D, Nackley, Andrea G
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Analgesia; Analgesics; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; Anesthesiology; Animals; Correlation analysis; Disease Models, Animal; Female; Gene expression; Gene Expression Regulation - drug effects; Genetic Variation; House mouse; Humans; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - genetics; Kinases; Male; Mice; Molecular chains; Molecular modelling; Morphine; Morphine - administration & dosage; Morphine - adverse effects; Morphine - pharmacology; Narcotics; Opioid receptors (type mu); Pain; Pain perception; Pain sensitivity; Proteins; Receptors, Opioid, mu - genetics; Rodents; Signaling; siRNA; Studies; Thermal stimuli
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135711

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. 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. 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.