The effect exerted by two γ-endorphin derivatives (DTγE and DEγE) 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=.5x10-8 M (Confidence limits: 3.7x10-8- 9.1x10-8). DTγE and DEγE per se (1x10-6-5x10-6-1x10-5 M) did not modify significantly the E.C. of guinea pig ileum. Furthermore, DTγE or DEγE 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 DTγE or DEγE (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 DTγE and IC50=7.7x10-7 M (Confidence limits: 2.7x10-6-8.7x10-7) for DEγE . The effect exerted by two β-endorphin fragments (DTγE and DEγE) was investigated on the acute opiate withdrawal induced by μ, k and δ receptor agonists in vitro. After a exposure in vitro for 4 min to morphine (less selective μ agonist), DAGO (highly selective μ agonist), U50-488H (highly selective k agonist) and β-endorphin (selective μ-δ 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 δ agonist). DTγE or DEγE injection before or after treatment with morphine, DAGO, U50-488H, β-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 DTγE or DEγE are able to reduce significantly opiate withdrawal in vitro, suggesting an important functional interaction beween β-endorphin fragments and opioid withdrawal at both μ, k and δ receptor level. Our results indicate that chronic treatment of guinea pigs with DTγE or DEγE 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 γ- endorphin derivatives and opioid system.