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Current Topics in Pharmacology   Volumes    Volume 7  Issue 1
Antagonism by dexamethasone of opiate withdrawal. A hypothesis for the development of opiate dependence
Anna Capasso
Pages: 1 - 16
Number of pages: 16
Current Topics in Pharmacology
Volume 7  Issue 1

Copyright © 2003 Research Trends. All rights reserved


The effect of dexamethasone on acute opiate withdrawal induced by µ, k and δ receptor agonists was investigated in vitro.

Following a 4 min in vitro exposure to morphine (less selective µ agonist), DAGO (highly selective µ agonist) and U50-488H (highly selective k agonist) a strong contracture of guinea-pig isolated ileum was observed after the addition of naloxone.  This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (highly selective δ  agonist).  Dexamethasone treatment before or after the opioid agonists tested was capable of both preventing and reverting the naloxone-induced contracture after exposure to µ opiate agonists morphine and DAGO in a concentration- and time-dependent fashion.  Also, the steroid reduced naloxone-induced contracture following the exposure to U50-488H only when injected before the k opiate agonist.  Finally, it did not affect the naloxone-contracture after exposure to deltorphin.

Pretreatment with RU-38486, a glucocorticoid receptor antagonist, inhibited dexamethasone antagonism on responses to both µ and k agonists whereas pretreatment with cyclohemixide, a protein synthesis inhibitor, blocked only the antagonistic effects of dexamethasone on responses to the µ opioid agonists.

In this respect, in order to establish the mechanism underlying DEX-opiate dependence interaction, the following experiments were considered:

a) the effect of neutralizing anti-lipocortin-1 antibody and a polyclonal anti-type II extracellular phospholipase A2 antibody on opiate withdrawal in vitro. The addition to the organ bath of a neutralizing anti-lipocortin-1 antibody, at a dilution of 1:10.000, prior to DEX addition, reverted the inhibitory effect of the steroid.  Furthermore, a polyclonal anti-type II extracellular phospholipase A2 antibody, in a dilution 1:1000, mimicked DEX inhibitory effect.

b) the effects of PLA2, COX1, COX2, and LIPO inhibitors on the opiate withdrawal in vitro.  Mepacrine (a PLA2 inhibitor), tolmetin (selective COX1 inhibitor) and meloxicam (selective COX2 inhibitor) treatment before or after morphine were able of both preventing and reversing the naloxone-induced contracture after exposure to morphine in a concentration-dependent fashion.  Also, NDGA (5-lipoxygenase inhibitor) was able to block naloxone-induced contracture following the exposure to morphine both if injected before or after the opioid agonist.

c) the role of NF-kB in the expression of opiate withdrawal by using the PDTC, an inhibitor of NF-kB activation.

PDTC (1x10-8-5x10-8-1x10-7 M) was able to reduce the naloxone-induced contracture after exposure to the opioid agonist in a concentration-dependent fashion.

Overall, these data indicate that dexamethasone induces significative effects on µ-mediated opiate withdrawal in vtiro,  suggesting an important functional interaction between corticosteroids and the opioid system primarly at the µ receptor level.  The ability of RU-3486 and cycloheximide to block dexamethasone effects indicate that the steroid interference on µ-mediated withdrawal involves protein syntheses dependent-mechanism via glucocorticoid receptor.  Our results suggest that DEX effects in this in vitro model of opiate withdrawal is due to extracellular type II PLA2 inhibition through lipocortin-1 thus confirming that arachidonic acid and its metabolites (prostaglandins and leukotrienes) are involved in the development of opioid withdrawal. Finally, also NF-kB is involved in the expression of opiate withdrawal thus extending and explaining previous papers performed with dexamethasone and selective arachidonic acid metabolites inhibitors. 
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