The interaction between cannabinoids and opioids has been widely evaluated because of the diverse physiological effects shared by both types of compounds, including antinociception, hypothermia, and control of locomotion, rewarding properties and the ability to induce drug abuse. Interestingly, the interaction between these two systems seems to be bi-directional. Thus, morphine-induced intravenous self-administration (Ledent et al. 1999; Cossu et al. 2001) and conditioned place preference (Martin et al. 2002) was abolished in knockout mice lacking the CB1 cannabinoid receptors. These studies underlie the relevance of CB1 cannabinoid receptors for the manifestation of the reinforcing properties of morphine. The ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a period of extinction has been also evaluated. The cannabinoid agonists WIN55,212-2 and CP55,940, but not THC, restored heroin-seeking behaviour in rats, whereas the CB1 cannabinoid antagonist SR141716A completely prevented the reinstatement of drug-seeking behaviour induced by a priming injection of heroin (Fattore et al. 2003), supporting the cooperation between opioid and cannabinoid systems in the modulation of addictive behaviour.
Different pharmacological and molecular approaches have been used to investigate the interaction between cannabinoids and opioids in physical dependence. For example, administration of the CB1 cannabinoid antagonist SR141716A can precipitate behavioural and biochemical manifestations of withdrawal in morphine-dependent rats (Navarro et al. 2001). In contrast to these data, SR141716A did not precipitate any behavioural sign of withdrawal in morphine-dependent mice (Lichtman et al. 2001). These discrepancies could be due to the different animal species and/or differences in the experimental procedure. However, studies performed in CB1 knockout mice clearly demonstrated the important role played by the CB1 cannabinoid receptors in the physical manifestations of the morphine withdrawal syndrome. Thus, a robust decrease in the severity of naloxone-precipitated morphine withdrawal syndrome was reported in CB1 knockout mice (Ledent et al. 1999). In agreement, the co-administration of SR141716A and morphine over
5 days produced an important attenuation in the incidence of the morphine withdrawal manifestations (Mas-Nieto et al. 2001). Earlystudieshave also demonstrated that acute administration of cannabinoid agonists strongly attenuated the severity of morphine abstinence (Hine et al. 1975; Bhargava 1976a,b; Bhargava and Way 1976; Vela et al. 1995). Furthermore, a chronic pre-treatment with THC before starting chronic morphine administration reduced the somatic manifestations of naloxone-precipitated morphine withdrawal, without modifying the motivational responses of this opioid compound (Valverde et al. 2000b).
Reciprocally, the endogenous opioid system has been reported to be involved in the motivational responses and withdrawal manifestations induced by cannabi-noids. Thus, the rewarding effects induced by THC were abolished in p-opioid receptor knockout mice (Ghozland et al. 2002). Furthermore, the dysphoric effects induced by a high dose of THC (5 mg/kg) were slightly attenuated in p-knockout mice and completely blocked in mice lacking K-opioid receptors (Ghozland et al. 2002). The conditioned place aversion induced by a high dose of THC (5 mg/kg) was also abolished in prodynorphin knockout mice, also supporting the involvement of K-opioid receptors in the motivational responses induced by cannabinoids (Zimmer et al. 2001). In addition, the rewarding responses induced by THC in the conditioned place paradigm were also abolished in double knockout mice lacking both p- and ó-opioid receptors (Castañe et al. 2003). There is also evidence to suggest that the endogenous opioid system participates in the reinforcing properties of cannabinoids. Thus, the opioid antagonist naloxone partially blocked self-administration of the cannabinoid agonist CP55,940 (Braida et al. 2001). THC self-administration behaviour was also attenuated by a different opioid antagonist naltrexone (Justinova et al. 2004). Furthermore, naloxone precipitated some behavioural signs of abstinence in rats chronically treated with a cannabinoid agonist (Kaymakcalan et al. 1977; Navarro et al. 2001).
The role of the endogenous opioid peptides in cannabinoid dependence has also been investigated by using knockout mice. The expression of cannabinoid withdrawal was attenuated in THC-dependent knockout mice lacking the pre-proenkephalin gene (Valverde et al. 2000a). However, THC abstinence was not modified in p-, ó- or K-opioid receptor knockout mice (Ghozland et al. 2002). In contrast, another study reported a decrease in the severity of cannabinoid withdrawal syndrome in p-opioid receptor knockout mice (Lichtman et al. 2001). The different genetic construction of knockout mice and the changes in the experimental conditions can explain these discrepancies. Finally, a significant decrease in the severity of cannabinoid withdrawal syndrome was observed in double p-, ó-opioid receptor knockout mice (Castañe et al. 2003), suggesting that a cooperative action of p- and ó-opioid receptors is required for the entire expression of THC dependence.
All these results indicate that the bi-directional interactions between the endogenous cannabinoid and opioid systems are crucial for the motivational properties and the development of physical dependence induced by these two kinds of drugs, and could provide new strategies for a more rational approach to the treatment of drug abuse.
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