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), a 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 an 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 the pharmacological activity of D-Phe is not directly related to the endogenous opiate system.