The effects of D-phenylalanine and its derivatives on enkephalin degradation in vitro: relation to analgesia and attenuation of the morphine withdrawal syndrome.
The effect of D-Phenylalanine (D-Phe), putative carboxypeptidase A inhibitor and its four derivatives (T1-T4) on analgesia, development of tolerance and physical dependence to morphine, and on degradation of both exogenous and endogenous enkephalins was investigated. Systemic administration of either D-Phe or its derivatives produced naloxone-reversible analgesia in the hot-plate test in mice. Naloxone-precipitated morphine withdrawal syndrome was attenuated in mice after systemic subacute administration (7 days, 1.2 mmol/kg, sc) of D-phe derivatives, the development of tolerance to morphine being unchanged. In the presence of either D-Phe or its derivatives in incubation mixture (up to 10(-3) mol/l) the hydrolysis of exogenous 3H-Met5-and 3H-Leu5-enkephalin in striatal homogenates was slightly inhibited. Moreover, the addition of D-Phe or its derivatives seemed to increase the per cent of recovered endogenous Met5-enkephalin released from veratridine-depolarized striatal particles. In contrast, bestatin, an amino-peptidase inhibitor, and a mixture of dipeptides (Tyr-Tyr, Leu-Leu, Leu-Gly) markedly inhibited degradation of both endogenous and exogenous enkephalins in vitro. The results obtained in this study suggest that that pharmacological activity of D-Phe is not directly related to the endogenous opiate system.
D000700:Analgesics; D000818:Animals; D001711:Biotransformation; D003342:Corpus Striatum / Q000378:metabolism; D004361:Drug Tolerance; D004744:Enkephalin, Methionine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000037:antagonists & inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D014701:Veratridine / Q000494:pharmacology
D000700:Analgesics; D004745:Enkephalins; D009270:Naloxone; D010649:Phenylalanine; D004744:Enkephalin, Methionine; D014701:Veratridine; D009020:Morphine