Background: Planarians have mammalian-like neurotransmitter systems and have been established as a novel in vivo model for neuropharmacology. In previous research, planarians exposed to the cannabinoid receptor (CB-R) agonist WIN 55,212-2 (10 μmol/L) for 1 h displayed a significant (p < 0.05) decrease in spontaneous locomotor velocity (pLMV) when subsequently tested in drug-free, but not in drug-containing, water. This demonstrated abstinence-induced withdrawal from a CB-R agonist as a manifestation of the development of physical dependence. Purpose: The purpose of the present study was to extend previous work and to further establish a cannabinoid behavioral model with planarians. Specifically, the goals included (i) confirm the work with WIN 55,212-2 and extend to a second agonist (ii) interfere with agonist-induced physical dependence using several CB-R antagonists, (ii) demonstrate antagonist-induced precipitated withdrawal behavior, and (iii) try to induce withdrawal behavior from CB-R agonists using UV light. Methods: Two CB agonists (WIN 55,212-2 and JWH251) and four CB antagonists (AM251, AM281, SLV319 and SR144528) were used. Planarians were placed individually in CB-R agonist or agonist + antagonist mixtures for 20 and 30 min of exposure (with or without UV radiation), and withdrawal was quantified by measuring pLMV in drug-free vs drug-containing water (with or without UV light irradiation). Results: (i) Four different CB1-R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly blocked development of physical dependence induced by two different CB-R agonists (WIN 55,212-2 and JWH251). (ii) None of the same four antagonists (AM251, AM281, SLV319 and SR144528) precipitated withdrawal. (iii) Short wavelength (254 nm), but not long wavelength (366 nm), UV light attenuated abstinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal behavior. Conclusions: The results confirm the use of a planarian model as a simple yet robust way to study development of physical dependence to cannabinoid agonists. The model is more rapid and sensitive than the usual rodent models. The effect of UV irradiation adds to the supposition that the results are receptor-related. The results also give rise to the surprising suggestion, within the limitations of the methodology, that development of cannabinoid physical dependence and antagonist-induced precipitated withdrawal might be separable phenomena in planarians. / Pharmaceutical Sciences

The idea that humans and laboratory animals can become physically dependent on marijuana or its primary psychoactive constituent, delta-9-tetrahydrocannabinol (THC), is gaining acceptance. However, there are no currently approved pharmacotherapies to treat cannabinoid withdrawal. The objective of this thesis was to evaluate whether elevating endogenous anandamide levels using mice lacking fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide metabolism, would ameliorate THC dependence. Mice were treated subchronically with a low or high THC dosing regimen and challenged with the CB1 receptor antagonist, rimonabant, to precipitate withdrawal. Following subchronic THC treatment, rimonabant precipitated a significant increase in paw flutters that was dependent on THC dose. However, FAAH-/- mice displayed a similar magnitude of withdrawal responses as wild type control mice, regardless of subchronic dosing regimen. Finally, rimonabant was equipotent in precipitating withdrawal responses in both genotypes. Collectively, these results demonstrate that FAAH-/- and +/+ mice show identical THC dependence, thus arguing against the notion that elevating anandamide levels through FAAH suppression will reduce cannabinoid withdrawal.

No description available.

Introduction : La tolérance induite par l’utilisation prolongée des opiacés peut se traduire par un syndrome de sevrage aux opiacés (SDSO). Il n’existe aucun consensus sur la méthode idéale de sevrage des opiacés pour prévenir le SDSO chez la clientèle des soins intensifs pédiatriques (SIP). L’objectif de cette étude était de comparer l’efficacité de deux stratégies de sevrage des opiacés, à savoir la méthadone et la morphine administrées par voie entérale, à prévenir le SDSO. Devis : Essai clinique randomisé à double aveugle chez les enfants sous ventilation mécanique hospitalisés aux SIP. Méthode : Nous avons comparé la durée totale de sevrage, l’incidence et la sévérité du SDSO chez les enfants à risque au moins modéré de SDSO sevrés avec la méthadone et la morphine entérales. Les enfants inclus étaient ceux hospitalisés au Centre Hospitalier Universitaire Sainte-Justine ou au Centre Mère-Enfant Soleil de Québec entre le 1er novembre 2003 et le 31 mai 2009. Résultats : Quarante-huit patients (22 groupe méthadone et 26 groupe morphine) ont été inclus et 30 patients ont complété le protocole de sevrage (16 groupe méthadone et 14 groupe morphine). La durée médiane de sevrage était de 5.4 jours dans le groupe méthadone comparativement à 5.8 jours pour le groupe morphine (p=0.49). Il n’y avait pas de différence dans l’incidence du SDSO (62.5% versus 42.9%; p=0.46), et dans sa sévérité (12.5% versus 14.3% de SDSO sévère; p=0.62). Conclusion : L’efficacité d’un sevrage standardisé des opiacés par la méthadone était comparable à celle de la morphine. / Background : The prolonged use of opioids has been associated with opioid tolerance and weaning is necessary to prevent opioid withdrawal symptoms (OWS). Little research exist for an ideal effective opioid taper to reduce the prevalence of OWS. This study aim to compare the effectiveness of two opioid taper strategies, enteral’s methadone and morphine, in preventing the occurrence of OWS among pediatric intensive care patients. Design: Double-blinded randomized controlled trial in mechanically ventilated children (MVCs) hospitalized in 2 pediatric intensive care units (PICU). Methods: Eligible patients were MVCs at moderate risk of OWS admitted in PICU of the Centre Hospitalier Universitaire Sainte-Justine or the Centre Mère-Enfant Soleil de Québec between November 1, 2003 and May 31, 2009. We assessed the total weaning duration, the OWS’s incidence and the OWS’s severity in a methadone’s and a morphine’s taper schedule. Results: Forty-eight patients were included, 22 in the methadone group and 26 in the morphine group and 30 patients completed the weaning protocol (16 methadone and 14 morphine). The median duration of weaning was 5.4 days among methadone’s patients as opposed to 5.8 days among morphine’s group (p=0.49). There was no statistical difference between groups for OWS’s incidence (62.5% vs 42.9%; p=0.46), nor for its severity (12.5% vs 14.3% of severe OWS; p=0.62). Conclusion: The use of a standardized opioid weaning protocol with enteral methadone was as effective as the enteral morphine one’s to prevent OWS. Further studies are needed to determine an ideal opioid taper to reduce OWS.