TY - JOUR
T1 - Chronic morphine-mediated adenylyl cyclase superactivation is attenuated by the Raf-1 inhibitor, GW5074
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
UR - http://www.scopus.com/inward/record.url?scp=33745006794&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745006794&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2006.04.033
DO - 10.1016/j.ejphar.2006.04.033
M3 - Article
C2 - 16750187
AN - SCOPUS:33745006794
SN - 0014-2999
VL - 540
SP - 57
EP - 59
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -