Δ 9 -THC and related cannabinoids suppress substance P- induced neurokinin NK 1 -receptor-mediated vomiting via activation of cannabinoid CB 1 receptor.

Δ ⁹ -THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB ₁ receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT ₃ -and neurokinin NK ₁ -receptors to induce vomiting. Δ ⁹ -THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT ₃ receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ ⁹ -THC and related CB ₁ /CB ₂ receptor agonists (WIN55,212-2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK ₁ receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ ⁹ -THC (i.p. or s.c.), WIN55,212-2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ ⁹ -THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ ⁹ -THC against SP-induced vomiting was prevented by low non-emetic doses of the CB ₁ receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK ₁ receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ ⁹ -THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK ₁ receptor agonists via stimulation of cannabinoid CB ₁ receptors.
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