Therapeutic Potential of Targeting the Endocannabinoids: Implications for the Treatment of Obesity, Metabolic Syndrome, Drug Abuse and Smoking Cessation

University of Liverpool, Eleanor Rathbone Building, Bedford Street South, Liverpool L69 7ZA, UK.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2006; 13(22):2669-80. DOI: 10.2174/092986706778201512
Source: PubMed


Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.

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    • "Agonists of the 5-HT 2C receptor reduce food intake, weight gain, and several aspects of drug-taking behavior in laboratory animals (Grottick et al, 2000; Higgins and Fletcher, 2003). The cannabinoid CB1 receptor antagonist rimonabant similarly reduces feeding and behaviors related to drug abuse (Tucci et al, 2006). Peripherally localized peptide hormones such as leptin and ghrelin are critical for the maintenance of metabolic and energy homeostasis. "
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    ABSTRACT: Previously, we showed that the 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B. Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.
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    • "Our findings might also relate to previous reports of a vanilloid receptor-like response at hippocampal excitatory synapses (Al-Hayani et al., 2001; Hajos and Freund, 2002). SR141716A (also known as rimonabant or Acomplia) is in wide clinical use outside the United States as an antiobesity aid (Tucci et al., 2006; Padwal and Majumdar, 2007). A large percentage of patients stop taking this drug as a result of psychiatric side effects , and our findings suggest the possibility that some of the central effects of rimonabant result from the antagonism of TRPV1 receptors as well as CB1 receptors (Pegorini et al., 2006). "
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    ABSTRACT: TRPV1 receptors have classically been defined as heat-sensitive, ligand-gated, nonselective cation channels that integrate nociceptive stimuli in sensory neurons. TRPV1 receptors have also been identified in the brain, but their physiological role is poorly understood. Here we report that TRPV1 channel activation is necessary and sufficient to trigger long-term synaptic depression (LTD). Excitatory synapses onto hippocampal interneurons were depressed by either capsaicin, a potent TRPV1 channel activator, or the endogenously released eicosanoid, 12-(S)-HPETE, whereas neighboring excitatory synapses onto CA1 pyramidal cells were unaffected. TRPV1 receptor antagonists also prevented interneuron LTD. In brain slices from TRPV1-/- mice, LTD was absent, and neither capsaicin nor 12-(S)-HPETE elicited synaptic depression. Our results suggest that, in the hippocampus, TRPV1 receptor activation selectively modifies synapses onto interneurons. Like other forms of hippocampal synaptic plasticity, TRPV1-mediated LTD may have a role in long-term changes in physiological and pathological circuit behavior during learning and epileptic activity.
    Full-text · Article · Apr 2008 · Neuron
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    • "One result might be an increased likelihood of reuse or establishment of a self-medicating routine involving cannabis and/or other drugs of abuse (Butters, 2002; Newcomb and Harlow, 1986). Thus, it is noteworthy that CB 1 antagonists have found therapeutic applications in reducing recidivism in smokers (Cohen et al., 2005; Tucci et al., 2006) and other substance abusers (Maldonado et al., 2006). "
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    ABSTRACT: Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB(1) antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The converse was also true; acute Delta(9)-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Delta(9)-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.
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