Cannabinoid-Induced Hyperphagia is Mediated by Increased Meal Frequency and the Orexin-1 Receptor in Male Rats

• Published in: Pharmacology research & perspectives Vol. 13; no. 5; p. e70171
• Main Authors: Lord, Magen N, Madu, Grace C, Loera-Lopez, Ana L, Aaron, Alexander P, Lin, Jessica, Noble, Emily E
• Format: Journal Article
• Language: English
• Published: United States 01.10.2025
• Subjects: Animals; Benzoxazoles - pharmacology; Cannabinoid Receptor Agonists - administration & dosage; Cannabinoid Receptor Agonists - pharmacology; Cannabinoids - administration & dosage; Cannabinoids - pharmacology; Eating - drug effects; Feeding Behavior - drug effects; Hyperphagia - chemically induced; Hyperphagia - metabolism; Male; Naphthyridines - pharmacology; Neurons - drug effects; Neurons - metabolism; Orexin Receptor Antagonists - pharmacology; Orexin Receptors - metabolism; Orexins - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Sprague-Dawley; Urea - analogs & derivatives; Urea - pharmacology; foraging behavior; CB1; microstructure; meal patterns; hypocretin; c‐Fos; locomotor activity
• ISSN: 2052-1707
• DOI: 10.1002/prp2.70171

Exogenous cannabinoids have long been known to promote eating. However, the underlying mechanisms have not been completely elucidated, which is critical to understanding their utility. The orexin/hypocretin (OH) system of the lateral hypothalamus (LHA) has known anatomical, biochemical, and physiological interactions with the endocannabinoid system, and has an established role in promoting appetitive behavior; yet, it is still unknown if the OH system mediates food intake following cannabinoid administration. Herein, we validated an oral method of cannabinoid receptor agonist, CP55940, administration via gelatin-based edibles, showing that voluntarily consumed cannabinoid-containing edibles produce acute hyperphagia via an increase in meal number in male rats. Following cannabinoid administration, rats displayed an upregulation in the immediate early gene c-Fos in OH neurons compared to vehicle-treated animals. We further employed a within-subjects design to investigate whether orexin-1 (OX1) receptor signaling was necessary for cannabinoid-induced hyperphagia by coadministering a subeffective dose of an OX1 receptor antagonist, SB334867, with the cannabinoid-containing edible. Data were collected from metabolic monitoring cages, simultaneously capturing chow intake, locomotor activity, and metabolic variables. Results showed that the OX1 receptor antagonist blocked cannabinoid-induced hyperphagia and the transient increase in locomotor activity following cannabinoid administration. Furthermore, both the edible cannabinoid receptor agonist and the OX1 receptor antagonist individually reduced energy expenditure several hours following administration. Taken together, we conclude that the OX1 receptor is required for the hyperphagic response to exogenous cannabinoid administration.