The effect exerted by two
gamma-endorphin derivatives (
DTgammaE and
DEgammaE) was investigated on
morphine-induced inhibition on the electrically induced contractions of guinea pig ileum in vitro.
Morphine (1x10(-8)-5x10 (-8)-1x10 (-7) M) dose dependently and significantly reduced the E.C. of guinea pig ileum, IC50=6.5x10(-8) M (Confidence limits: 3.7x10 (-8)-9.1x10 (-8)).
DTgammaE and
DEgammaE per se (1x10 (-6)-5x10 (-6)-1x10 (-5) M) did not modify significantly the E.C. of guinea pig ileum. Furthermore,
DTgammaE or
DEgammaE injection 10-30-60 min before
morphine, did not affect the inhibitory effect of
morphine on the E.C. of guinea pig ileum. By contrast, ilea from guinea-pigs treated for 4 days with
DTgammaE or
DEgammaE (1 mg/Kg/i.p.) were less sensitive to the inhibitory effect of
morphine, IC50=8.3x10 (-7) M (Confidence limits: 1.4x10(-6)-3.5x10(-7)) for
DTgammaE and IC50=7.7x10(-7) M (Confidence limits: 2.7x10(-6)-8.7x10(-7 )) for
DEgammaE . The effect exerted by two
beta-endorphin fragments (
DTgammaE and
DEgammaE) was investigated on the acute
opiate withdrawal induced by micro, kappa and
delta receptor agonists in vitro. After a exposure in vitro for 4 min to
morphine (less selective micro agonist),
DAGO (highly selective micro agonist), U50-488H (highly selective kappa agonist) and
beta-endorphin (selective micro- delta agonist), a strong
contracture of isolated guinea pig ileum was observed after the addition of
naloxone. This effect was also observed when isolated rabbit jejunum was pretreated with
deltorphin (highly selective delta agonist).
DTgammaE or
DEgammaE injection before or
after treatment with
morphine,
DAGO, U50-488H,
beta-endorphin or
deltorphin was able of both preventing and reversing the
naloxone-induced
contracture after exposure to the
opioid agonists in a concentration-dependent fashion. Our results indicate that both
DTgammaE or
DEgammaE are able to reduce significantly
opiate withdrawal in vitro, suggesting an important functional interaction beween
beta-endorphin fragments and
opioid withdrawal at both micro, kappa and
delta receptor level. Our results indicate that chronic treatment of guinea pigs with
DTgammaE or
DEgammaE induces a significant reduction of the inhibitory effect of
morphine on the E.C. of guinea-pig ileum thus confirming an important functional interaction between
gamma-endorphin derivatives and
opioid system.