Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074

Xu Yue; Eva V. Varga; Dagmar Stropova; Todd W. Vanderah; Henry I. Yamamura; William R. Roeske

doi:10.1016/j.ejphar.2006.04.033

Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074

Xu Yue, Eva V. Varga, Dagmar Stropova, Todd W. Vanderah, Henry I. Yamamura, William R. Roeske

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human μ-opioid receptor. We found that pretreatment of CHO cells stably expressing the human μ-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 μM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.

Original language	English (US)
Pages (from-to)	57-59
Number of pages	3
Journal	European Journal of Pharmacology
Volume	540
Issue number	1-3
DOIs	https://doi.org/10.1016/j.ejphar.2006.04.033
State	Published - Jul 1 2006

Keywords

Adenylyl cyclase superactivation
Human μ-opioid receptor
Raf-1

ASJC Scopus subject areas

Pharmacology

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10.1016/j.ejphar.2006.04.033

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title = "Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074",

abstract = "The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human μ-opioid receptor. We found that pretreatment of CHO cells stably expressing the human μ-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 μM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.",

keywords = "Adenylyl cyclase superactivation, Human μ-opioid receptor, Raf-1",

author = "Xu Yue and Varga, {Eva V.} and Dagmar Stropova and Vanderah, {Todd W.} and Yamamura, {Henry I.} and Roeske, {William R.}",

note = "Funding Information: We thank Michelle Thatcher and Magda Kaczmarska for maintaining the CHO cell culture. This work was supported in part by grants from the Arizona Disease Control Research Commission and the National Institute of Health.",

year = "2006",

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doi = "10.1016/j.ejphar.2006.04.033",

language = "English (US)",

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AU - Yue, Xu

AU - Varga, Eva V.

AU - Stropova, Dagmar

AU - Vanderah, Todd W.

AU - Yamamura, Henry I.

AU - Roeske, William R.

N1 - Funding Information: We thank Michelle Thatcher and Magda Kaczmarska for maintaining the CHO cell culture. This work was supported in part by grants from the Arizona Disease Control Research Commission and the National Institute of Health.

PY - 2006/7/1

Y1 - 2006/7/1

N2 - The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human μ-opioid receptor. We found that pretreatment of CHO cells stably expressing the human μ-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 μM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.

AB - The utility of morphine for the treatment of chronic pain is limited by the development of analgesic tolerance. Adenylyl cyclase (AC) superactivation, induced by chronic opioid agonist administration, is regarded as one of the molecular mechanisms leading to tolerance. In the present work, we tested the role of Raf-1 in morphine-mediated AC superactivation in CHO cells stably expressing the human μ-opioid receptor. We found that pretreatment of CHO cells stably expressing the human μ-opioid receptor with the selective Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW5074, 10 μM, 60 min) completely abolished chronic morphine-mediated AC superactivation (P < 0.01). This finding indicates that Raf-1 may have a crucial role in compensatory feedback regulation of cellular cAMP levels by clinically important opioid analgesics.

KW - Adenylyl cyclase superactivation

KW - Human μ-opioid receptor

KW - Raf-1

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Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074

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