Involvement of Raf-1 in chronic delta-opioid receptor agonist-mediated adenylyl cyclase superactivation

Eur J Pharmacol. 2002 Sep 6;451(1):101-2. doi: 10.1016/s0014-2999(02)02220-3.


Chronic delta-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human delta-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic delta-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 microM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n = 6, P < 0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / metabolism*
  • Animals
  • CHO Cells
  • Colforsin / pharmacology*
  • Cricetinae
  • Enzyme Activation
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Receptors, Opioid, delta / agonists*


  • Receptors, Opioid, delta
  • Colforsin
  • Proto-Oncogene Proteins c-raf
  • Adenylyl Cyclases