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Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB1 antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB1 antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB1 antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB1 receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB1 antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction. Keywords: Cannabinoid, morphine, dependence, κ opioid systems, mice Introduction Since drug addiction is often considered as a chronic, relapsing disorder, several therapeutical assays to reduce craving are under investigation. In the case of opiate addicts, long-term treatment with opioid agonists such as methadone or buprenorphine, are currently used (review in Kreek, 1997; Fischer et al., 1999; Ward et al., 1999). Nevertheless, there are several reasons why it should be of great interest to use non-opioid substances for maintenance treatments or detoxification of heroin abusers. Firstly, like heroin, methadone and buprenorphine used in maintenance program could generate a psychological dependence and can be diverted to illegal sales. Secondly, as an opioid agonist, methadone is able to trigger a withdrawal syndrome and even though it is less severe than that observed with heroin, it is longer lasting. Furthermore, physical dependence has also been reported to occur after chronic buprenorphine treatment (Kuhlman et al., 1998; Dyer et al., 1999). Opioids and cannabinoids share several pharmacological properties (Dewey, 1986), both leading for example to analgesia (Lichtman & Martin, 1991), hypothermia (Anderson et al., 1975) and reduced locomotor activity at high doses (Anderson et al., 1975). Moreover, several lines of evidence support the occurrence of interactions between both systems (Welch et al., 1995; Tanda et al., 1997; Meng et al., 1998; Ambrosio et al., 1999; reviews in Manzanares et al., 1999; Piomelli et al., 2000). This has been recently confirmed by evaluating the pharmacological properties of morphine in central cannabinoid receptor (CB1) knockout mice (Ledent et al., 1999). Thus, the acute effects of morphine were unaffected in CB1 knockout mice as compared to wild type animals, whereas reinforcing properties of the alkaloid and severity of the withdrawal syndrome were found to be reduced, suggesting that long-term CB1 antagonist administration could be considered for preventing the development of dependence to opiates. However, frequent inconsistencies between observed and expected results are found in knockout mice, probably due to compensatory developmental mechanisms occurring during embryogenesis and early postnatal life (Zimmer et al., 1998; de Felipe et al., 1998). It was therefore of interest to investigate the effect resulting from the blockade of the CB1 receptors by an antagonist using wild type mice. The synthesis of the highly potent and selective CB1 antagonist, SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxy-amide (Rinaldi-Carmona et al., 1994) affords the possibility to evaluate this hypothesis and to determine whether chronic blockade of CB1 receptors could be used to facilitate drug abstinence. We have therefore studied the behavioural changes classically observed following chronic morphine treatment i.e. withdrawal syndrome and rewarding properties (review in Koob & Le Moal, 1997) in mice repeatedly treated with the combination morphine+SR 141716A. Moreover, as numerous studies have reported a link between both κ and cannabinoid systems (Smith et al., 1994; Welch, 1997) we have evaluated the effects of chronic SR 141716A treatment on the levels of κ endogenous opioid peptide, dynorphin, as well as κ opioid receptors. Indeed, stimulation of κ opioid receptors in the nucleus accumbens was shown to negatively modulate the rewarding properties of morphine. This occurs by a decrease in synaptic levels of dopamine induced by opioid activation of the mesolimbic dopaminergic pathway (Di Chiara & Imperato, 1988; Spanagel et al., 1992; Kuzmin et al., 1997). |
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