Genetic dissociation of morphine analgesia from hyperalgesia in mice.
BACKGROUND
Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM).


OBJECTIVE
This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions.


METHODS
Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays.


RESULTS
Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphine analgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine-induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion.


CONCLUSIONS
Together, our findings confirm the established role of 7TM mu receptor variants in morphine analgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence.
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.|Department of Neurology and Neuroscience, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA.
Gina F
GF
Marrone
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Valerie
V
Le Rouzic
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Andras
A
Varadi
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Jin
J
Xu
Department of Neurology and Neuroscience, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA.
Anjali M
AM
Rajadhyaksha
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Susruta
S
Majumdar
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.
Ying-Xian
YX
Pan
Department of Neurology and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA. pasterng@mskcc.org.|Department of Neurology and Neuroscience, Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA. pasterng@mskcc.org.
Gavril W
GW
Pasternak
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use*; D000071184:Pharmacogenomic Variants / Q000187:drug effects / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics*
D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D009020:Morphine
6TM; Alternative splicing; GPCR; KNOCKOUT; MOR-1; Mu opioid; Mu opioid receptor; Truncated