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


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.
Center of Pain Research and Innovation, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States of America.
Folabomi A
FA
Oladosu
Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
Matthew S
MS
Conrad
Center of Pain Research and Innovation, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States of America.
Sandra C
SC
O'Buckley
Department of Biostatistics, University of North Carolina-Chapel Hill, Chapel Hill, NC United States of America.
Naim U
NU
Rashid
Center of Pain Research and Innovation, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States of America.
Gary D
GD
Slade
Center of Pain Research and Innovation, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States of America.
Andrea G
AG
Nackley
D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000235:genetics*
D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D009020:Morphine