Functional Interference of Dexamethasone on Some Morphine Effects: Hypothesis for the Steroid-Opioid Interaction: An Updated

The effect of dexamethasone (DEX) and its interaction with morphine has been studied on transmurally-stimulated guinea-pig ileum preparation, gastrointestinal transit, analgesia, withdrawal and hypotension.

Transmurally-stimulated guinea-pig ileum preparation: DEX dose-dependently reduced the contractions of the ileum. Proteic synthesis inhibitors did not modify the inhibition induced by DEX whereas RU-38486, a glucocorticoid antagonist receptor, antagonized completely the inhibitory effect of DEX.

Gastrointestinal transit: DEX was found to antagonize morphine-, atropine- and verapamil-induced constipation. Cycloheximide does not modify the DEX effects. RU-38486 reverses both the inhibitory action of DEX on gastrointestinal transit and its reducing effect on morphine-induced constipation.

Analgesia: DEX reduced the antinociception induced by mu agonists, morphine, DAMGO and beta endorphin whereas the steroid exerted little or no influence on the antinociception induced by a delta1 agonist, DPDPE and delta2 agonist deltorphin II. DEX potentiated the antinociception induced by the K agonist, U50,488.

Cycloheximide, a protein synthesis inhibitor, prevented the antagonism by DEX of responses to the mu opioid agonists. Finally, i.c.v. injection of DEX significantly reduced morphine analgesia in Swiss mice whereas no effects were observed in DBA/2J and C57BL/6 mice. In addition, i.p. injection of DEX significantly reduced morphine analgesia in all three strains.

Withdrawal: DEX 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 DEX antagonism on responses to both µ and k agonists whereas pretreatment with cycloheximide, a protein synthesis inhibitor, blocked only the antagonistic effects of dexamethasone on responses to the µ opioid agonists.

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.

Hypotension: DEX per se at a dose of 7.5 µmol/kg, i.v. did not significantly modify the mean arterial blood pressure of animals. DEX administration 90 min, but not 30 or 60 min, before the opioid agonists injection, prevented the hypotension induced by morphine or U50-488H, but not that induced by DAGO or deltorphin II. Pretreatment with RU-38486 (mifepristone; 7.5 μmol/kg, i.v.), a glucocorticoid receptor antagonist, 15 min before the steroid, prevented DEX inhibition of hypotension induced by morphine and U50-488H. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor (3.5 μmol/kg, i.v.), was also able to abolish the effects of DEX on morphine- and U50-488H-induced hypotension. Our data indicate that in the both in vivo and in vitro models there is an important functional interaction between the corticosteroid and the opioid systems at least at the mu. receptor level, while delta and K receptors are modulated in different ways. These results strongly confirm a functionalinteraction between DEX and opiods system.

Keywords: Dexamethasone, morphine, transmurally-stimulated guinea-pig ileum preparation, gastrointestinal transit, analgesia, withdrawal, hypotension