A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

Enquist, Johan; Kim, Joseph A.; Bartlett, Selena E.; Ferwerda, Madeline; Whistler, Jennifer L.

doi:10.1124/jpet.111.179754

Cited by 17 publications

(13 citation statements)

References 22 publications

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“…This possibility is further supported by a mutant DMOR mouse model in which a portion of exon 3-encoded sequences in mMOR-1 was replaced by a portion of the C terminus of the δ opioid receptor mDOR-1 with the elimination of all the C-terminal downstream from exon 3, similarly to our mE3M mice (53). As with our mice, the DMOR animals developed tolerance to morphine more rapidly than WT controls.…”

Section: Discussionsupporting

confidence: 52%

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Xu¹,

Lu²,

Narayan³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 52%

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Xu¹,

Lu²,

Narayan³

et al. 2017

Journal of Clinical Investigation

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“…C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and allowed at least 1 week to acclimatize upon arrival. DMOR knockin mice were generated as described previously (Enquist et al, 2011) and kept with wild-type (WT) littermates. All animal experiments were performed in accordance with the guidelines of the Ernest Gallo Clinic and Research Center Institutional Animal Care and Use Committee.…”

Section: Materials Morphine Sulfate Pentahydrate Was Purchased From mentioning

confidence: 99%

“…If this were the case, we would expect methadone to produce substantial tolerance if the MOR could not be recycled. To examine this possibility we used mice expressing a mutant form of the MOR, DMOR (for degrading MOR) that is targeted for degradation after endocytosis (Finn and Whistler, 2001;Enquist et al, 2011).…”

Section: Methadone Causes Fewer Side Effects Than Morphine 387mentioning

confidence: 99%

“…Although many studies have shown that the MOR is primarily recycled after endocytosis (Finn and Whistler, 2001;Whistler et al, 2002;Minnis et al, 2003;Yu et al, 2010), the hypothesis persists that receptor down-regulation also contributes to opioid tolerance (Ueda and Ueda, 2009). We have generated a knockin mouse that expresses a mutant version of the MOR, DMOR, for degrading MOR, that recruits arrestin, endocytoses, and is sorted for degradation in response to both morphine and methadone (Finn and Whistler, 2001;Whistler et al, 2002;Enquist et al, 2011). Thus, the DMOR animal model allowed us to investigate the impact of MOR down-regulation on tolerance to methadone and morphine.…”

Section: Introductionmentioning

confidence: 99%

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Chronic Methadone Treatment Shows a Better Cost/Benefit Ratio than Chronic Morphine in Mice

Enquist¹,

Ferwerda²,

Milan‐Lobo³

et al. 2011

J Pharmacol Exp Ther

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Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading -opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

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“…However, morphine is relatively inefficient at producing acute desensitization in live neurons (Alvarez et al, 2002;Bailey et al, 2003Bailey et al, , 2009bDang and Williams, 2005;Arttamangkul et al, 2008). Therefore, the role of desensitization in tolerance to morphine has been questioned (Finn and Whistler, 2001;Enquist et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Morphine Desensitization and Cellular Tolerance Are Distinguished in Rat Locus Ceruleus Neurons

Levitt

Williams

2012

Mol Pharmacol

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ABSTRACT-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance.

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A Novel Knock-In Mouse Reveals Mechanistically Distinct Forms of Morphine Tolerance

Cited by 17 publications

References 22 publications

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

Chronic Methadone Treatment Shows a Better Cost/Benefit Ratio than Chronic Morphine in Mice

Morphine Desensitization and Cellular Tolerance Are Distinguished in Rat Locus Ceruleus Neurons

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