TY - JOUR
T1 - Effects of morphine on forskolin-stimulated pro-enkephalin mRNA levels in rat striatum
T2 - a model for acute and chronic opioid actions in brain
AU - Kluttz, Bryan W.
AU - Vrana, Kent E.
AU - Dworkin, Steven I.
AU - Childers, Steven R.
N1 - Funding Information:
We thank Dr. Steven Sabol for providing the pro-enkephalin mRNA probe. The authors also thank Tim Koves and Tammy Sexton for valuable technical assistance. This work was partially supported by PHS Grant DA-06634 from the National Institute on Drug Abuse.
PY - 1995/9
Y1 - 1995/9
N2 - Opioid agonists inhibit adenylyl cyclase in brain through Gi-coupled receptors. One potential biological role for this reaction would be to decrease pro-enkephalin mRNA synthesis by decreasing intracellular cAMP levels and preventing stimulation of gene expression via the cAMP regulatory element (CRE). To determine whether such effects occur in vivo, rats were injected i.c.v. with a water-soluble analog of forskolin, 7-0-deacetyl-7β[γ-(morpholino)-butyryl] forskolin (DMB-forskolin), to stimulate the CRE. Pro-enkephalin mRNA levels were assayed in striatum by Northern blot analysis. The treatment with the forskolin analog increased striatal pro-enkephalin mRNA levels approximately 2-fold in 4 h. When rats were injected with morphine (20 mg/kg i.p.) 1 h before DMB-forskolin administration, the stimulation of pro-enkephalin mRNA levels was eliminated. This acute effect of morphine was blocked by co-administration with 10 mg/kg naloxone. When rats were chronically treated with morphine for 8 days, then injected with morphine (20 mg/kg i.p.) 1 h before DMB-forskolin administration, the inhibitory effect of morphine was lost (i.e. DMB-forskolin increased pro-enkephalin mRNA levels by 2 fold in either control and morphine-treated rats). These data not only demonstrate the in vivo relevance of opioid-inhibited adenylyl cyclase in the control of pro-enkephalin mRNA levels, but also show that this model is useful for studying how this signal transduction system is attenuated during the development of tolerance.
AB - Opioid agonists inhibit adenylyl cyclase in brain through Gi-coupled receptors. One potential biological role for this reaction would be to decrease pro-enkephalin mRNA synthesis by decreasing intracellular cAMP levels and preventing stimulation of gene expression via the cAMP regulatory element (CRE). To determine whether such effects occur in vivo, rats were injected i.c.v. with a water-soluble analog of forskolin, 7-0-deacetyl-7β[γ-(morpholino)-butyryl] forskolin (DMB-forskolin), to stimulate the CRE. Pro-enkephalin mRNA levels were assayed in striatum by Northern blot analysis. The treatment with the forskolin analog increased striatal pro-enkephalin mRNA levels approximately 2-fold in 4 h. When rats were injected with morphine (20 mg/kg i.p.) 1 h before DMB-forskolin administration, the stimulation of pro-enkephalin mRNA levels was eliminated. This acute effect of morphine was blocked by co-administration with 10 mg/kg naloxone. When rats were chronically treated with morphine for 8 days, then injected with morphine (20 mg/kg i.p.) 1 h before DMB-forskolin administration, the inhibitory effect of morphine was lost (i.e. DMB-forskolin increased pro-enkephalin mRNA levels by 2 fold in either control and morphine-treated rats). These data not only demonstrate the in vivo relevance of opioid-inhibited adenylyl cyclase in the control of pro-enkephalin mRNA levels, but also show that this model is useful for studying how this signal transduction system is attenuated during the development of tolerance.
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U2 - 10.1016/0169-328X(95)00100-7
DO - 10.1016/0169-328X(95)00100-7
M3 - Article
C2 - 7500843
AN - SCOPUS:0029160065
SN - 0169-328X
VL - 32
SP - 313
EP - 320
JO - Molecular Brain Research
JF - Molecular Brain Research
IS - 2
ER -