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P.6.d.001 Effect of ORL1 receptor activation on opioid- and psychostimulant-induced conditioned place preference in rats
S588
P.6.d. Addiction − Drugs (basic)
Discussion: After systemic administration GBL is rapidly converted to GHB(gammahydroxybutyrate). GBL itself is biologically inactive [1]. GHB has a half-life of 20 to 30 minutes and can be detected in urine for up to 12 hours. According to a recent review the mean duration for acute GHB/GBL withdrawal is 6−10 days. Benzodiazepines in high doses are the first line treatment. In cases refractory to benzodiazepines, pentobarbital or propofol are said to be effective [2]. The patient in this case suffered an acute GBL withdrawal syndrome for a period of about 3 weeks despite intensive treatment. The withdrawal syndrome included changing levels of alertness and orientation, delirium with aggressive behaviour and hallucination, tachycardia, hypertension, strong nausea and muscle pain. This findings correlate with those described in other cases of GHB and GBL withdrawal [2]. An additional benzodiazepine withdrawal cannot be precluded as a possible contributor to the long duration. However the predominant vegetative symptoms of strong nausea and muscle pain were known to the patient as typical symptoms from former GBL withdrawals. Valproate is considered as usefull treatment for severe hyperactive delirium, when conventional therapy is inadequate. It is known to enhance GABAergic neurotransmission and has been shown to raise endogenous GHB levels in rat brain [3]. However, up to now there was no evidence that valproate is effective in the treatment of GHB/GBL withdrawal. To our knowledge this is the first report showing a clear positive effect of valproate. This case illustrates that severe GBL withdrawal can last as long as three weeks, and that in treatment resistant cases valproate might be an option. References [1] Roth, R.H., Delgado, J.M.R., Giarman, N.J., 1966 GammaButyrolactone and gamma-hydroxybutyric acid. The pharmacologically active form. Int J Neuropharmacol 5, 421−8. [2] Wojtowicz, J.M., 2008 Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systemic review. CJEM 10(1), 69−74. [3] Johannessen, L.C., 2008 Antiepileptic drugs in non-epilepsy disorders: relation between mechanism of action and clinical efficacy. CNS Drugs 22(1), 27−4.
P.6.d. Addiction − Drugs (basic) P.6.d.001 Effect of ORL1 receptor activation on opioid- and psychostimulant-induced conditioned place preference in rats K. Rutten1 ° , J. De Vry1 , W. Bruckmann1 , T.M. Tzschentke1 . 1 Gr¨ unenthal GmbH, Department of Pharmacology, Aachen, Germany Evidence from pharmacological studies suggests that the endogenous nociceptin/ orphanin FQ system, acting via the activation of the ORL1 (Opioid Receptor-Like 1 or Nociceptin/OrphaninFQNOP) receptor may counteract the rewarding effect of opioids and possibly of other drugs of abuse. For example, it was demonstrated that intracerebroventricular administration of nociceptin inhibits the rewarding effect of morphine in the conditioned place preference (CPP) paradigm in mice [1] and rats [2] . Furthermore the systemically administered ORL1 receptor agonist Ro64–6198 blocked the acquisition of morphine-induced CPP in mice [3] .
In order to further investigate the behavioural mechanism underlying the reward-attenuating effect of the Nociceptin/OrphaninFQ system, we systematically investigated the effect of the ORL1 receptor agonist Ro65–6570 on the acquisition of CPP induced by various opioids and psychostimulants in rats, under standardized experimental conditions. First, the motivational effect of Ro64– 6198 (0.316–3.16 mg/kg i.p.) and Ro65–6570 (1−10 mg/kg i.p.), when administered alone in the CPP procedure, was assessed. Ro65–6570 was selected for further drug combination studies since, unlike Ro64–6198, it was devoid of an intrinsic motivational effect. Next, the minimal effective dose (MED) to induce CPP for the opioids heroin (0.1–3.16 mg/kg i.p.), morphine (1−10 mg/kg i.p.), hydrocodone (0.316−10 mg/kg i.p.), tilidine (1–31.6 mg/kg i.p.), hydromorphone (0.1−10 mg/kg i.p.), and oxycodone (0.0316−10 mg/kg i.p.), as well as the psychostimulants cocaine (3.16–31.6 mg/kg i.p.), dexamphetamine (0.316– 3.16 mg/kg i.p.), and nicotine (0.1–0.316 mg/kg s.c.), combined with the vehicle of Ro65–6570, was assessed. Finally, the MED to induce CPP for the above mentioned opioids and psychostimulants in combination with Ro65–6570 (3.16 mg/kg i.p.) was determined. Ro65–6570 (3.16 mg/kg i.p.) or its vehicle was administered directly before each drug or, in an additional experiment, 15min before the drug. We found that all drugs produced CPP, and that for each opioid and cocaine, but not for dexamphetamine and nicotine, the MED was higher when the drug was combined with Ro65– 6570 (3.16 mg/kg i.p.) than when combined with vehicle. A final experiment demonstrated that attenuation of the rewarding effect of tilidine (3.16 mg/kg i.p.) and oxycodone (1 mg/kg i.p.) by Ro65–6570 (3.16 mg/kg i.p.) was reversed by pre-treatment with the ORL1 receptor antagonist J-1133970 (4.64 mg/kg i.p.), suggesting that the attenuating effect of Ro65–6570 on opioidinduced CPP is due to activation of the ORL1 receptor. These findings confirm previously published data that activation of the ORL1 receptor has a negative modulatory impact on the effect of drugs of abuse on the brain reward system. Together, this strengthens the suggestion that ORL1 receptor agonists have antiabuse effects. It appears however that the anti-abuse effect of such compounds may not apply to all classes of drugs of abuse in a similar manner, as it was found that activation of ORL1 receptors more effectively and consistently attenuates the rewarding effect of opioids than that of psychostimulants. References [1] Sakoori, K., Murphy, N.P., 2008, Expression of morphine-conditioned place preference is more vulnerable than naloxone-conditioned place aversion to disruption by nociceptin in mice. Neurosci Lett 443, 108– 112. [2] Ciccocioppo, R., Angeletti, S., Sanna, P.P., Weiss, F., Massi, M., 2000, Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol 404, 153–159. [3] Shoblock, J.R., Wichmann, J., Maidment, N.T., 2005, The effect of a systemically active ORL-1 agonist, Ro 64–6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference. Neuropharmacology 49, 439–446.
P.6.d. Addiction − Drugs (basic)
Discussion: After systemic administration GBL is rapidly converted to GHB(gammahydroxybutyrate). GBL itself is biologically inactive [1]. GHB has a half-life of 20 to 30 minutes and can be detected in urine for up to 12 hours. According to a recent review the mean duration for acute GHB/GBL withdrawal is 6−10 days. Benzodiazepines in high doses are the first line treatment. In cases refractory to benzodiazepines, pentobarbital or propofol are said to be effective [2]. The patient in this case suffered an acute GBL withdrawal syndrome for a period of about 3 weeks despite intensive treatment. The withdrawal syndrome included changing levels of alertness and orientation, delirium with aggressive behaviour and hallucination, tachycardia, hypertension, strong nausea and muscle pain. This findings correlate with those described in other cases of GHB and GBL withdrawal [2]. An additional benzodiazepine withdrawal cannot be precluded as a possible contributor to the long duration. However the predominant vegetative symptoms of strong nausea and muscle pain were known to the patient as typical symptoms from former GBL withdrawals. Valproate is considered as usefull treatment for severe hyperactive delirium, when conventional therapy is inadequate. It is known to enhance GABAergic neurotransmission and has been shown to raise endogenous GHB levels in rat brain [3]. However, up to now there was no evidence that valproate is effective in the treatment of GHB/GBL withdrawal. To our knowledge this is the first report showing a clear positive effect of valproate. This case illustrates that severe GBL withdrawal can last as long as three weeks, and that in treatment resistant cases valproate might be an option. References [1] Roth, R.H., Delgado, J.M.R., Giarman, N.J., 1966 GammaButyrolactone and gamma-hydroxybutyric acid. The pharmacologically active form. Int J Neuropharmacol 5, 421−8. [2] Wojtowicz, J.M., 2008 Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systemic review. CJEM 10(1), 69−74. [3] Johannessen, L.C., 2008 Antiepileptic drugs in non-epilepsy disorders: relation between mechanism of action and clinical efficacy. CNS Drugs 22(1), 27−4.
P.6.d. Addiction − Drugs (basic) P.6.d.001 Effect of ORL1 receptor activation on opioid- and psychostimulant-induced conditioned place preference in rats K. Rutten1 ° , J. De Vry1 , W. Bruckmann1 , T.M. Tzschentke1 . 1 Gr¨ unenthal GmbH, Department of Pharmacology, Aachen, Germany Evidence from pharmacological studies suggests that the endogenous nociceptin/ orphanin FQ system, acting via the activation of the ORL1 (Opioid Receptor-Like 1 or Nociceptin/OrphaninFQNOP) receptor may counteract the rewarding effect of opioids and possibly of other drugs of abuse. For example, it was demonstrated that intracerebroventricular administration of nociceptin inhibits the rewarding effect of morphine in the conditioned place preference (CPP) paradigm in mice [1] and rats [2] . Furthermore the systemically administered ORL1 receptor agonist Ro64–6198 blocked the acquisition of morphine-induced CPP in mice [3] .
In order to further investigate the behavioural mechanism underlying the reward-attenuating effect of the Nociceptin/OrphaninFQ system, we systematically investigated the effect of the ORL1 receptor agonist Ro65–6570 on the acquisition of CPP induced by various opioids and psychostimulants in rats, under standardized experimental conditions. First, the motivational effect of Ro64– 6198 (0.316–3.16 mg/kg i.p.) and Ro65–6570 (1−10 mg/kg i.p.), when administered alone in the CPP procedure, was assessed. Ro65–6570 was selected for further drug combination studies since, unlike Ro64–6198, it was devoid of an intrinsic motivational effect. Next, the minimal effective dose (MED) to induce CPP for the opioids heroin (0.1–3.16 mg/kg i.p.), morphine (1−10 mg/kg i.p.), hydrocodone (0.316−10 mg/kg i.p.), tilidine (1–31.6 mg/kg i.p.), hydromorphone (0.1−10 mg/kg i.p.), and oxycodone (0.0316−10 mg/kg i.p.), as well as the psychostimulants cocaine (3.16–31.6 mg/kg i.p.), dexamphetamine (0.316– 3.16 mg/kg i.p.), and nicotine (0.1–0.316 mg/kg s.c.), combined with the vehicle of Ro65–6570, was assessed. Finally, the MED to induce CPP for the above mentioned opioids and psychostimulants in combination with Ro65–6570 (3.16 mg/kg i.p.) was determined. Ro65–6570 (3.16 mg/kg i.p.) or its vehicle was administered directly before each drug or, in an additional experiment, 15min before the drug. We found that all drugs produced CPP, and that for each opioid and cocaine, but not for dexamphetamine and nicotine, the MED was higher when the drug was combined with Ro65– 6570 (3.16 mg/kg i.p.) than when combined with vehicle. A final experiment demonstrated that attenuation of the rewarding effect of tilidine (3.16 mg/kg i.p.) and oxycodone (1 mg/kg i.p.) by Ro65–6570 (3.16 mg/kg i.p.) was reversed by pre-treatment with the ORL1 receptor antagonist J-1133970 (4.64 mg/kg i.p.), suggesting that the attenuating effect of Ro65–6570 on opioidinduced CPP is due to activation of the ORL1 receptor. These findings confirm previously published data that activation of the ORL1 receptor has a negative modulatory impact on the effect of drugs of abuse on the brain reward system. Together, this strengthens the suggestion that ORL1 receptor agonists have antiabuse effects. It appears however that the anti-abuse effect of such compounds may not apply to all classes of drugs of abuse in a similar manner, as it was found that activation of ORL1 receptors more effectively and consistently attenuates the rewarding effect of opioids than that of psychostimulants. References [1] Sakoori, K., Murphy, N.P., 2008, Expression of morphine-conditioned place preference is more vulnerable than naloxone-conditioned place aversion to disruption by nociceptin in mice. Neurosci Lett 443, 108– 112. [2] Ciccocioppo, R., Angeletti, S., Sanna, P.P., Weiss, F., Massi, M., 2000, Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol 404, 153–159. [3] Shoblock, J.R., Wichmann, J., Maidment, N.T., 2005, The effect of a systemically active ORL-1 agonist, Ro 64–6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference. Neuropharmacology 49, 439–446.