The effect of
dexamethasone on acute
opiate withdrawal induced by mu, kappa and
delta receptor agonists was investigated in vitro. After a 4-min in vitro exposure to
morphine (less selective mu agonist), D-Ala2-N-methyl-Phe4-Gly5-ol)-
enkephalin (
DAGO; highly selective mu agonist) and trans(+/-)-3,4-dichloro-N-methyl-N-[2(1-pyrrolidynyl)cyclohexyl]- benzeneacetamide (
U50-488H; highly selective kappa 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 delta agonist).
Dexamethasone treatment before or after the
opioid agonists tested was capable of both preventing and reverting the
naloxone-induced
contracture after exposure to mu
opiate agonists
morphine and
DAGO in a concentration- and time-dependent fashion. Also, the
steroid reduced
naloxone-induced
contracture after the exposure to
U50-488H only when injected before the kappa
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 mu and kappa agonists, whereas pretreatment with
cycloheximide, a
protein synthesis inhibitor, blocked only the antagonistic effects of
dexamethasone on responses to the mu
opioid agonists. Overall, these data indicate that
dexamethasone induces significant effects on mu-mediated
opiate with-drawal in vitro, which suggest an important functional interaction between
corticosteroids and the
opioid system primarily at the
mu receptor level. The ability of
RU-38486 and
cycloheximide to block
dexamethasone effects indicates that the
steroid interference on mu-mediated withdrawal involves a
protein synthesis-dependent mechanism via
glucocorticoid receptor.