Role of the stress response and the endocannabinoid system in Δ-tetrahydrocannabinol (THC)-induced nausea.

Rationale: Dysregulation of the endocannabinoid (eCB) system by high doses of Δ-tetrahydrocannabinol (THC) is hypothesized to generate a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis contributing to cannabinoid hyperemesis syndrome (CHS).

Objectives And Methods: Using the conditioned gaping model of nausea, we aimed to determine if pre-treatments that interfere with stress, or an anti-emetic drug, interfere with THC-induced nausea in male rats. The corticotropin-releasing hormone (CRH) antagonist, antalarmin, was given to inhibit the HPA axis during conditioning. Since eCBs inhibit stress, MJN110 (which elevates 2-arachidonylglycerol (2-AG)) and URB597 (which elevates anandamide (AEA)) were also tested. Propranolol (β-adrenergic antagonist) and WAY-100635 (5-HT antagonist) attenuate HPA activation by cannabinoids and, therefore, were assessed. In humans, CHS symptoms are not alleviated by anti-emetic drugs, such as ondansetron (5-HT antagonist); however, benzodiazepines are effective. Therefore, ondansetron and chlordiazepoxide were tested. To determine if HPA activation by THC is dose-dependent, corticosterone (CORT) was analyzed from serum of rats treated with 0.0, 0.5, or 10 mg/kg THC.

Results: Antalarmin (10 and 20 mg/kg), MJN110 (10 mg/kg), URB597 (0.3 mg/kg), propranolol (2.5 and 5 mg/kg), WAY-100635 (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) interfered with THC-induced conditioned gaping, but the anti-emetic ondansetron (0.1 and 0.01 mg/kg) did not. THC produced significantly higher CORT levels at 10 mg/kg than at 0.0 and 0.5 mg/kg THC.

Conclusions: Treatments that interfere with the stress response also inhibit THC-induced conditioned gaping, but a typical anti-emetic drug does not, supporting the hypothesis that THC-induced nausea, and CHS, is a result of a dysregulated stress response.