title: Morphine-induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence.
abstract: Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence.
authors.affiliation: Ernest Gallo Clinic & Research Center, 5858 Horton St., Suite 200, Emeryville, California 94608, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kim
authors.forename: Selena
authors.initials: S
authors.lastname: Bartlett
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Carsten K
authors.initials: CK
authors.lastname: Nielsen
authors.forename: Amy M
authors.initials: AM
authors.lastname: Chang
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Maria
authors.initials: M
authors.lastname: Waldhoer
authors.forename: Chrissi J
authors.initials: CJ
authors.lastname: Ou
authors.forename: Stacy
authors.initials: S
authors.lastname: Taylor
authors.forename: Madeline
authors.initials: M
authors.lastname: Ferwerda
authors.forename: Dragana
authors.initials: D
authors.lastname: Cado
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000818:Animals; D004361:Drug Tolerance; D004705:Endocytosis / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D017450:Receptors, Opioid, mu; D009020:Morphine