title: A novel knock-in mouse reveals mechanistically distinct forms of morphine tolerance.
abstract: The role of μ-opioid receptor (MOR) down-regulation in opioid tolerance remains controversial. In this study, we used a novel knock-in mouse to examine how changing the extent of MOR down-regulation alters the development of morphine tolerance. These mice express a mutant MOR, degrading MOR (DMOR), that differs from the wild-type (WT) MOR in two ways: 1) unlike the recycling WT MOR, the mutant DMOR is targeted for degradation after its internalization, thus facilitating down-regulation; and 2) unlike the WT MOR, DMOR is efficiently internalized in response to morphine activation. We found that both WT MOR and DMOR mice develop tolerance to morphine, but DMOR mice exhibit a more rapid onset of tolerance and show receptor down-regulation. WT MOR mice develop morphine tolerance more slowly but even once profoundly tolerant show no receptor down-regulation. Furthermore, WT mice show significantly more morphine dependence than DMOR mice after long-term treatment as indicated by withdrawal. Taken together these data indicate that tolerance mediated by receptor down-regulation manifests differently both at the behavioral and biochemical level than does the actual morphine tolerance that occurs in WT mice and that loss of receptor function is not a major contributor to morphine tolerance in WT MOR mice.
authors.affiliation: Ernest Gallo Clinic and Research Center, 5858 Horton St., Emeryville, CA 94608, USA.
authors.forename: Johan
authors.initials: J
authors.lastname: Enquist
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kim
authors.forename: Selena
authors.initials: S
authors.lastname: Bartlett
authors.forename: Madeline
authors.initials: M
authors.lastname: Ferwerda
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004361:Drug Tolerance / Q000235:genetics*; D005260:Female; D055879:Gene Knock-In Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009020:Morphine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009021:Morphine Dependence / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D017450:Receptors, Opioid, mu; D009020:Morphine