European Journal of Pharmacology, 194 (1991) 17-23 © 1991 Elsevier Science Publishers B.V. 0014-2999/91/$03.50 ADONIS 001429999100174L 17 EJP 51739 The neutral endopeptidase-24.11 inhibitor SCH 34826 does not change opioid binding but reduces D 1 dopamine receptors in rat brain Maria Trampus, Ennio Ongini, Katia Varani 1 and Pier Andrea Borea 1 Research Laboratories, Schering-Plough S.p.A., 1-20060 Comazzo, Milan, Italy and z Institute of Pharmacology, University of Ferrara, 1-44100, Ferrara, Italy Received 31 October 1990, accepted 4 December 1990 The effect of repeated administration of the neutral endopeptidase-24.11 (NEP) inhibitor SCH 34826 on the kinetic properties of opioid and dopamine binding in the rat cerebral cortex and striatum was investigated. SCH 34826, given at 100 and 300 mg/kg orally twice a day for 14 days, did not alter either Bma x or K d for the #, 8 or x opioid receptor type in the cortex, as measured by studying binding parameters for the #-selective ligand [3H][D-Ala2,Me-Phe4,Gly(ol)5]enkephalin (DAGO), the 8-selective ligand [3H][D-Pen2,D-PenS]enkephalin (DPDPE) and the x ligand [3H]ethylketazocine (EKC). SCH 34826 reduced significantly the number of D a dopamine receptors labeled with [3H]SCH 23390 in the striatum (Bma x was 90 and 84% of controls at 100 and 300 mg/kg, respectively). The number of D 2 receptors, measured by [3H]spiperone binding, was unaltered. The K d values for both receptor types were not affected. The data demonstrate that chronic inhibition of enkephalin degradation by SCH 34826 does not alter opioid receptors, whereas it reduces the number of O a receptors. These findings provide further support for the role of opioids in modulating central dopaminergic systems. As a reduction in the number of O a receptors is an effect common to antidepressant treatments, the antidepressant potential of NEP inhibitors should be investigated. Opioid receptors; Dopamine receptors; Dopamine D 1 receptors; Neutral endopeptidase-24.11 inhibitors; SCH 34826; Brain (rat); (Binding) 1. Introduction Inhibitors of the neutral endopeptidase-24.11 (EC 3.4.24.11) (NEP), prevent the degradation of endoge- nous enkephalins and therefore could have different effects at the level of the CNS (Schwartz et al., 1985). The enzyme is also referred to as 'enkephalinase', which is the trivial name given to it by Malfroy et al. (1979). An inhibitor of this enzyme, namely SCH 34826 [(S)-N- [N-[1-[[(2,2-dimethyl-l,3-dioxolan-4yl)methoxy]carbon- yl]-2-phenylethyl]-L-phenylalanyl]-fl-alanine], has been found to possess naloxone-reversible analgesic proper- ties in a variety of animal models (Chipkin et al., 1988). Unlike classic opioid drugs, SCH 34826 is devoid of undesirable effects, such as respiratory and gastroin- testinal depression (Chipkin et al., 1988), addiction lia- bility (Chipkin et al., 1989) or sedative properties (Trampus et al., 1990). By blocking the breakdown of enkephalins, SCH 34826 should maintain the en- kephalinergic tone evoked by stressors or painful stimuli. Correspondence to: M. Trampus, Schering-Piough S.p.A., Research Laboratories, 1-20060 Comazzo MI, Italy. The 8 opioid receptor, which is specifically activated by enkephalins (Paterson et al., 1983), is probably im- plicated in the action of SCH 34826 and other drugs of this class. Based on this pattern of activity, NEP inhibi- tors would be expected to produce the behavioral and neurochemical effects which typically accompany chronic administration of enkephalin analogs, such as [D-Ala2,D-LeuS]enkephalin (DADLE) which has been found to produce signs of physical dependence in rats and changes of 8 receptor characteristics in their brain cortex (Tao et al., 1988). However, chronic treatment with SCH 34826 (Chip- kin et al., 1989) or acetorphan (Lecomte et al., 1986) induces neither tolerance to the pharmacological activ- ity of these drugs nor dependence. There are no studies available showing effects on opioid receptors. It is not clear whether repeated stimulation of opioid receptors leads to specific changes in their characteristics. The issue is still controversial and there are data showing either no change (Robson et al., 1983; Martin, 1984) or definite modifications of opioid receptor characteristics following repeated administration of either morphine, ethorphine or DADLE (Danks et al., 1988; Tao et al., 1988; Brady et al., 1989; Werling et al., 1989).