Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence

Joseph A. Kim, Selena Bartlett, Li He, Carsten K. Nielsen, Amy M. Chang, Viktor Kharazia, Maria Waldhoer, Chrissi J. Ou, Stacy Taylor, Madeline Ferwerda, Dragana Cado, Jennifer Whistler

Research output: Contribution to journalArticle

62 Citations (Scopus)

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) [1], which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro [2-5] and in vivo [6-11]. 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.

Original languageEnglish (US)
Pages (from-to)129-135
Number of pages7
JournalCurrent Biology
Volume18
Issue number2
DOIs
StatePublished - Jan 22 2008
Externally publishedYes

Fingerprint

morphine
mu Opioid Receptor
endocytosis
Endocytosis
Morphine
narcotics
receptors
mice
Opioid Analgesics
analgesics
Analgesics
Switches
Ligands
drugs
Signal transduction
Recycling
Cell membranes
analgesia
G-proteins
GTP-Binding Proteins

Keywords

  • MOLNEURO

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence. / Kim, Joseph A.; Bartlett, Selena; He, Li; Nielsen, Carsten K.; Chang, Amy M.; Kharazia, Viktor; Waldhoer, Maria; Ou, Chrissi J.; Taylor, Stacy; Ferwerda, Madeline; Cado, Dragana; Whistler, Jennifer.

In: Current Biology, Vol. 18, No. 2, 22.01.2008, p. 129-135.

Research output: Contribution to journalArticle

Kim, JA, Bartlett, S, He, L, Nielsen, CK, Chang, AM, Kharazia, V, Waldhoer, M, Ou, CJ, Taylor, S, Ferwerda, M, Cado, D & Whistler, J 2008, 'Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence', Current Biology, vol. 18, no. 2, pp. 129-135. https://doi.org/10.1016/j.cub.2007.12.057
Kim, Joseph A. ; Bartlett, Selena ; He, Li ; Nielsen, Carsten K. ; Chang, Amy M. ; Kharazia, Viktor ; Waldhoer, Maria ; Ou, Chrissi J. ; Taylor, Stacy ; Ferwerda, Madeline ; Cado, Dragana ; Whistler, Jennifer. / Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence. In: Current Biology. 2008 ; Vol. 18, No. 2. pp. 129-135.
@article{6cd4e96c907948769ddec135992a7899,
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) [1], which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro [2-5] and in vivo [6-11]. 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.",
keywords = "MOLNEURO",
author = "Kim, {Joseph A.} and Selena Bartlett and Li He and Nielsen, {Carsten K.} and Chang, {Amy M.} and Viktor Kharazia and Maria Waldhoer and Ou, {Chrissi J.} and Stacy Taylor and Madeline Ferwerda and Dragana Cado and Jennifer Whistler",
year = "2008",
month = "1",
day = "22",
doi = "10.1016/j.cub.2007.12.057",
language = "English (US)",
volume = "18",
pages = "129--135",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence

AU - Kim, Joseph A.

AU - Bartlett, Selena

AU - He, Li

AU - Nielsen, Carsten K.

AU - Chang, Amy M.

AU - Kharazia, Viktor

AU - Waldhoer, Maria

AU - Ou, Chrissi J.

AU - Taylor, Stacy

AU - Ferwerda, Madeline

AU - Cado, Dragana

AU - Whistler, Jennifer

PY - 2008/1/22

Y1 - 2008/1/22

N2 - 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) [1], which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro [2-5] and in vivo [6-11]. 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.

AB - 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) [1], which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro [2-5] and in vivo [6-11]. 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.

KW - MOLNEURO

UR - http://www.scopus.com/inward/record.url?scp=38349074858&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38349074858&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2007.12.057

DO - 10.1016/j.cub.2007.12.057

M3 - Article

C2 - 18207746

AN - SCOPUS:38349074858

VL - 18

SP - 129

EP - 135

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 2

ER -