Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK₁ receptor antagonist

Abstract

1. The effects of GR205171, a selective tachykinin NK₁ receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet.

2. Animals receiving cisplatin (5.5 mg kg⁻¹, i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0_−15 min), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg⁻¹), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg⁻¹) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n=8), 0.3 (n=16) or 1.0 (n=13) mg kg⁻¹. In eight additional piglets, GR205171 (1 mg kg⁻¹) was administered 15 min before the onset of the delayed phase (T16_−15 min). A further five piglets received GR205171 (1 mg kg⁻¹) every 6 h throughout the experiment.

3. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0_−15 min, and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0_−15 min with GR205171 1 mg kg⁻¹, eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg⁻¹) at T16_−15 min exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171.

4. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

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