Inhibition of Fatty Acid Amide Hydrolase (FAAH) Reduces Contextually Elicited Gaping, a Measure of Anticipatory Nausea in Rats
Notice bibliographique
Résumé
Introduction: Chemotherapy-induced nausea and vomiting are among the most challenging and troubling symptoms reported in patients receiving chemotherapy. Reports have suggested the involvement of the endocannabinoid system (including FAAH inhibition) in acute and anticipatory nausea (AN), a conditional association between treatment cues such as the clinic setting and the experience of nausea. In the current study, IW-7229, a potent, indole ketoamide FAAH inhibitor, was assessed in a rat model of AN. Methods: Rats were given 4 pairings of a novel context with lithium chloride (LiCl), and then 72 hours after the final pairing, were given a test for AN. For the AN test trial, they received either (a) intragastric (ig) pretreatments of vehicle (VEH) or IW-7229 (10, 30 or 100 mg/kg), or (b) they received a pretreatment of VEH or IW-7229 (10 mg/kg, ig), followed by an additional pretreatment of either VEH or a CB1 antagonist, SR141716 (2.5 mg/kg, ip). Two hours following the pretreatment, rats were placed in the conditioning chamber for 5 minutes while their orofacial reactions were videotaped and later scored for the number of gapes. Immediately following the AN test, rats were given a 15-min locomotor activity test to assess whether the drug produced any motor impairments. Results: IW-7229 (10 or 30 mg/kg, but not 100 mg/kg) reduced contextually elicited gaping reactions by 77% and 64% relative to VEH controls, respectively. The effect of IW-7229 (10 mg/kg) on reducing contextually-elicited gaping reactions was completely blocked by administration of SR141716. These effects occurred without producing any locomotor effects at the effective doses (10 or 30 mg/kg of IW-7229); however, at 100 mg/kg, IW-7229 did reduce locomotor activity (21% reduction relative to VEH controls). Conclusion: Inhibition of FAAH, with the FAAH inhibitor IW-7229 (10 and 30 mg/kg), reduces AN in rats, and this effect appears to be CB1 receptor-mediated, likely due to elevated endogenous anandamide levels that result from FAAH inhibition. These data support the potential utility of IW-7229 in AN and, as proof of concept has not yet been demonstrated for FAAH inhibition in the clinic, provide a novel avenue to pursue in its clinical development. Disclosure - Dr. Profy, Dr. Currie, and Dr. Segal are employees of Ironwood Pharmaceuticals. Dr. Carey is an employee of Teleos Therapeutics. This research was funded by Ironwood Pharmaceuticals.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».