The effect on motion sickness and oculomotor function of GR 38032F, a 5‐ HT3‐receptor antagonist with anti‐emetic properties.

Abstract

1. The 5‐hydroxytryptamine (5‐HT3) receptor antagonist, GR 38032F, which possesses potent anti‐emetic properties in vomiting induced by cancer chemotherapeutic drugs, has been tested to determine its value in the prophylaxis of motion sickness induced by cross‐coupled stimulation. The double‐blind trial compared GR 38032F with both a placebo (lactose) and with hyoscine. In addition, studies of ocular pursuit and saccadic eye movements were carried out following the administration of each drug. 2. The prophylactic effect of GR 38032F on motion‐induced nausea was indistinguishable from that of placebo, whereas following hyoscine subjects showed a highly significant (P less than 0.001) increase in tolerance to cross‐coupled stimulation. Tests of oculomotor function showed no effect on saccadic eye movement from either drug. However, both drugs produced a significant (P less than 0.05) though small reduction in eye velocity gain during pursuit eye movement. 3. These findings suggest that the 5‐HT3 receptor is not involved in the neural pathways that bring about motion sickness, but that it may have a role in the control of ocular pursuit. The absence of an anti‐motion sickness effect from a drug that is effective in the treatment of vomiting induced by cancer chemotherapy serves to emphasize that different neural mechanisms are involved in the generation of motion sickness.

The Effect of Apomorphine, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) and Placebo on Smooth Pursuit Gain and Corrective Saccades in Normal Subjects

“…Stott et al (1989) studied the effect of ondanse tron, a 5-HT3 antagonist, on smooth pursuit in normal volunteers and found a small, but statistically significant reduction in gain; however, this effect of ondansetron may be related to effects on the OA system, because 5-HT3 antagonists have been shown to be extremely potent in antagonizing the behavioral consequences of increased mesolimbic OA activity (Costall et al 1990). This notion assumes that increased mesolimbic OA is associated with increased gain.…”

The broad‐spectrum anti‐emetic activity of the novel non‐peptide tachykinin NK1 receptor antagonist GR203040

“…In an experimental context, 5-HT3 receptor antagonists are very effective anti-emetic agents against cisplatin-or radiation-induced emesis, but are ineffective against orally administered copper sulphate (Rudd et al, 1990;Kamato et al, 1991), or systemic administration of morphine (Thompson et al, 1992;Pitkanen et al, 1993). Moreover, 5-HT3 receptor antagonists have been shown to be ineffective against the emesis evoked by motion in both animals and man (Lucot, 1989;Stott et al, 1989).…”

Serotonin Mechanisms in Chemotherapy-Induced Emesis in Cancer Patients

“…Granisetron, tropisetron, on dansetron, M DL72222, zatosetron, zacopridc and others have been shown to have antiemetic activity in patients with cancer exposed to different chemotherapeutic agents [ The possibility that the 5-HTs receptor antagonists exert a general, nonspecific, antiemetic action is unlikely, since these drugs fail to block emesis induced by the dopa mine agonist, apomorphine, and by loperamide, cholecystokinin and motion [3,6,7], Therefore, these observa tions suggest that in human patients, serotonin acting through 5-H T 3 receptors mediates the emetic response to chemo-and radiation therapy.…”