Clinical Interest in Enkephalin Degrading Enzyme Inhibitors in Opioid Addiction Treatment

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Addiction involves the compulsive seeking of the drug (craving), caused both by its reinforcing or rewarding effects and by the unpleasant experience (i.e., abstinence syndrome) produced by the sudden interruption of its consumption. It is important to emphasize that, in contrast to tolerance or physical dependence, which could be explained by events occurring at the receptor level, addiction is more complicated. Thus, psychological, environmental, and social factors can strongly influence its development. All these factors could explain the important variability among addicts to reach drug abstinence. Many approaches have been developed to help addicts interrupt their drug consumption. It seems that a combination of psychological assistance and pharmacotherapy has been so far the most efficient treatment, the most difficult problem remaining the strong susceptibility to relapse.

It has been suggested that the craving and self-administration of drugs could be explained either by a preexisting deficit in the endogenous opioid system or by a deficit that could occur after chronic administration of opiates. This hypothesis is in agreement with recent results (40) showing an important increase of Met-enkephalin outflow in morphine-dependent rats as compared to control animals in the periaqueductal gray (PAG), which contains high levels of <x-receptors as well as NEP and APN (12,14), and could be an important site of action for the development of physical dependence (27,41). This large increase in synaptic levels of enkephalin tone leads to a new state of the enkephalinergic neural circuitry that is not modified following naloxone-precipi-tated withdrawal syndrome. This lack of compensatory increase in extracellular amounts of endogenous enkephalins could participate in the withdrawal syndrome. Consistent with this hypothesis, an increase in endogenous enkephalins induced by peptidase inhibitors was shown to reduce the severity of the withdrawal syndrome in rats (27,42), and direct injection of enkephalins in rodent brain reduced morphine withdrawal (43).

Nevertheless, although early abstinence syndrome may be an important clinical problem, the most difficult aspect of the treatment of addiction is the protracted abstinence syndrome, one of the main factors contributing to relapse. Indeed, in the first days after cessation of prolonged drug use an acute withdrawal syndrome is observed, which consists of physiological changes (i.e., agitation, hyperalgesia, tachycardia, hypertension, diarrhea, and vomiting) and a variety of phenomena, i.e., cardiovascular, visceral, thermoregulatory, and subjective changes including a depressive state that may persist for months or more after the last dose of opiate. Thus, the main challenge in the management of opioid addiction is to develop a pharmacotherapy to minimize the short-term withdrawal syndrome and protracted opiate abstinence syndrome. Compounds used classically for clinical treatment of opiate withdrawal, such as clonidine and methadone, were investigated using a spontaneous abstinence, and their effects were compared with those of RB 101. As previously mentioned, methadone is the opiate agonist most currently used for maintenance treatment, and the D2-adrenoceptor agonist, clonidine, is the most effective nonopioid drug for improving some aspects of opiate withdrawal (44).

As expected, the effect of clonidine was limited to spontaneous withdrawal, while methadone was effective in reducing the withdrawal syndrome and appeared to be an efficient treatment in the maintenance period (45). The responses induced by RB 101 in this model of spontaneous withdrawal were similar to those induced by methadone (45) (Fig. 4). Thus, RB 101 could be particularly interesting as a therapeutic alternative in the maintenance of opiate addicts, especially to avoid methadone-dependence risk. Moreover, interestingly, it has been suggested that defects in the endogenous opioid systems might be involved in the etiology of depression. Accordingly, the behavioral responses triggered by forced swimming, conditioned suppression of motility, and learned helplessness, which are currently used as animal tests to screen antidepres-sants, were attenuated by treatment with dual inhibitors (46-50). These experiments have demonstrated that the inhibitors could modulate the functioning of the meso-corticolimbic and nigrostriatal dopaminergic systems, which are implicated in mood control and connected with enkephalin pathways. In line with this finding, the increased levels of endogenous enkephalins induced by RB 101 produce antidepressant-like effects, which were suppressed by both the Qopioid antagonist naltrindole and the dopamine D1 antagonist SCH23390 (47) (Fig. 5).

Furthermore, in a recent study we have shown that the Met-enkephalin outflow in the nucleus accumbens is modified by the induction of psychic dependence using the conditioned place preference paradigm, which is a test considered closer to addictive situations in humans than the self-administration procedure (51). In this experiment, rats with cannulae implanted in the nucleus accumbens for microdialysis were confined alternatively in distinct compartments under reinforced (morphine) or nonreinforced (saline) treatments. Using this model, opposite changes in the Met-enkephalin outflow were observed after a conditioning period of 6 d. Thus, Met-enkephalin level was found to be enhanced in the drug-paired compartment and reduced in the saline-paired one (40) (Fig. 6). The transient increase in enkephalin efflux observed in the nucleus accumbens when the animals were placed in the drug-paired compartment during the

Fig. 4. Global withdrawal score of spontaneous morphine abstinence before substitutive treatments evaluated 36 h after the last injection of morphine, or after substitutive treatments (twice daily for 4 d) with (1) saline; (2) clonidine (0.025 mg/kg); (3) methadone (2 mg/kg); (4) RB 101 (40 mg/kg). **p < 0.01 vs value of the same group before substitutive treatment, **p < 0.01 vs value of saline in the same session.

Fig. 4. Global withdrawal score of spontaneous morphine abstinence before substitutive treatments evaluated 36 h after the last injection of morphine, or after substitutive treatments (twice daily for 4 d) with (1) saline; (2) clonidine (0.025 mg/kg); (3) methadone (2 mg/kg); (4) RB 101 (40 mg/kg). **p < 0.01 vs value of the same group before substitutive treatment, **p < 0.01 vs value of saline in the same session.

Protracted Withdrawal Syndrome
Fig. 5. Conditioned suppression of motility test in mice. Effects of naltrindole (delta antagonist) and SCH 23390 (D1 antagonist) on the effects induced by iv injected RB 101.

microdialysis experiment may reflect an anticipation of the rewarding effect, associated with the memory of the reinforcing effects obtained with morphine in this compartment during the conditioning phase. In contrast, when the rats were placed in the saline-paired compartment, a decrease in the extracellular level of Met-enkephalin was observed, which may be related to an aversive effect. Consistent with these results, several studies have clearly demonstrated a role for endogenous opioid peptides in the perception of reward and in the mediation of behavioral reinforcement. Thus, it has been shown that water deprivation induced a reduction in opioid release, and that this effect was reversed in animals receiving water (52). On the other hand, rats isolated

Fig. 6. Extracellular levels of enkephalins in the nucleus accumbens of rats chronically treated with morphine in the place preference test to induce a psychic dependence. Briefly, the conditioning apparatus used in this experiment consisted of a rectangular plexiglas box divided into two square compartments of the same size (45 45 30 cm). Two distinctive sensory cues differentiated the compartments: the wall coloring (black or stripes), and the floor texture (grid or smooth). The protocole consisted of three phases. (1) Habituation (preconditioning) phase (1 d): drug-naive rats had free access to both compartments of the conditioning apparatus. (2) Conditioning phase (6 d). on alternate days each animal was injected with morphine (5 mg/kg ip) and confined in one compartment (d 1, 3, and 5) for 30 min, or injected with saline and confined in the other compartment (d 2, 4, and 6) for 30 min. Control groups were injected with saline every day and placed alternatively in both compartments. At the end of the conditioning phase (on d 7) rats were connected to the microdialysis pumps and 2 h after the beginning of the perfusion, two samples were collected to determine the basal efflux of neuropeptides. Then animals were transferred in conditioning apparatus and two microdialysis samples were collected.

Fig. 6. Extracellular levels of enkephalins in the nucleus accumbens of rats chronically treated with morphine in the place preference test to induce a psychic dependence. Briefly, the conditioning apparatus used in this experiment consisted of a rectangular plexiglas box divided into two square compartments of the same size (45 45 30 cm). Two distinctive sensory cues differentiated the compartments: the wall coloring (black or stripes), and the floor texture (grid or smooth). The protocole consisted of three phases. (1) Habituation (preconditioning) phase (1 d): drug-naive rats had free access to both compartments of the conditioning apparatus. (2) Conditioning phase (6 d). on alternate days each animal was injected with morphine (5 mg/kg ip) and confined in one compartment (d 1, 3, and 5) for 30 min, or injected with saline and confined in the other compartment (d 2, 4, and 6) for 30 min. Control groups were injected with saline every day and placed alternatively in both compartments. At the end of the conditioning phase (on d 7) rats were connected to the microdialysis pumps and 2 h after the beginning of the perfusion, two samples were collected to determine the basal efflux of neuropeptides. Then animals were transferred in conditioning apparatus and two microdialysis samples were collected.

and submitted to repetitive mild stress and then placed in presence of a congener (a situation considered fearful) have shown a lack of enkephalin release in the nucleus accumbens as compared to controls (53).

The increase of opioids observed when rats were placed in the morphine-paired compartment may contribute to the perception of reward. Thus, injection of enkephalin in the nucleus accumbens may serve as reinforcement for self-administration behavior (54,55), and an increased level of endogenous opioid peptides was observed when the compulsive seeking for drugs of abuse is high in the self-administration procedure (56,57).

The regulation of endogenous opioid peptides observed suggests that enkephalins may be a neural substrate for reward expectation, as already suggested for dopamine

(58,59). A signal may be deliver when the animal is placed in the drug-paired compartment, increasing the release of enkephalins, which may influence the processing of predictions and the choice of reward-maximizing action. This process may be either (a) dopamine-independent, involving only opioid receptors localized postsynaptically in the nucleus accumbens, as previously demonstrated in the maintenance of heroin self-administration (60), or (b) dopamine-dependent, consistent with the demonstration that activation of a> or Qopioid receptors in the nucleus accumbens increased dopamine release (61,62). Thus, activation of a> and/or Qopioid receptors by high levels of enkephalins may lead to an increased release of dopamine, while reduction of their stimulation by a lower amounts of opioid peptides may reduce the dopamine tone, resulting in a subsequent decrease in the activity of D1 receptors present in the nucleus accumbens. This regulation of extracellular dopamine efflux may be important in the expression of morphine-induced psychic dependence, as opioid reward measured by the conditioned place preference paradigm depends on midbrain dopamine-related mechanisms (63,64).

The social contexts in which drug addiction occurred and withdrawal syndrome was undergone are critically important. It is well established that reexposure to the conditioned environmental cues that had initially been associated with drug use can be a major factor causing persistent or recurrent drug cravings and relapses.

Thus, it could be speculated that when the drug abuser is reexposed to few of behavioral and social-context cue components associated with the use of drugs, a cascade of biochemical modifications occurs in the brain, with an increase of enkephalins in the limbic system, as observed by microdialysis when rats were placed in the drug-paired compartment. These modifications are assumed to participate in the control of emotions and feeling of pleasure. The increase of endogenous opioid peptides, which may reflect reward expectation, is short-lasting, and may be very quickly followed by a "distress" state. To avoid this negative effect the addict will self-administer drug to maintain activation of the hedonic pathway and even to increase it. Based on this hypothesis, the dual inhibitors of enkephalin-degrading enzymes may be proposed as a new therapy in opioid addiction, increasing the half-life of the endogenous pentapep-tides (Fig. 7). This seems to be confirmed by preliminary results showing that RB 101 is able to strongly reduce the number of heroin administrations in the model of self-administrations in rats (E. Ambrosio, personnal communication).

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