Palonosetron Uniquely Inhibits Substance P-Mediated Neuronal Responses in Rat Nodose Ganglia.

Clinical studies have shown that palonosetron is more effective than first generation 5-HT₃ receptor antagonists (5HT₃RAs) for preventing chemotherapy induced nausea and vomiting (CINV). In addition, NK-1 receptor antagonists have been shown to augment the the antiemetic activity of the 5HT₃RAs and dexamethasone to inhibit CINV. While palonosetron is effective in preventing delayed CINV, it does not directly bind to the NK-1 receptor. Recent data, however, has revealed significant receptor “cross-talk” between the NK-1 and 5HT₃ signaling pathways. Alteration of 5HT₃ receptor activity has been shown to cause downstream effects on NK-1 signaling, and vice versa. We postulated that if palonosetron differentially inhibited the NK-1/5HT₃ crosstalk, this could help explain the differences observed in the clinic.

We carried out in vivo electrophysiology experiments in rats where single neuronal recordings of nodose ganglia expressing both NK-1 and 5HT₃ receptors were collected.

First, we showed that neuronal responses to substance P (SP), a known non-selective agonist of the NK-1 receptor, were significantly enhanced in the presence of cisplatin. Second, we found that palonosetron, but not ondansetron or granisetron (1^st generation 5HT₃RAs), could dose-dependently inhibit the cisplatin-induced SP enhancement. This inhibition was observed when palonosetron was administered 30 minutes before or 5 or 10 h after cisplatin administration.

The results are consistent with previous mechanism of action (MOA) experiments indicating that palonosetron uniquely exhibits allosteric binding, positive cooperativity and receptor internalization at the 5HT₃ receptor. Taken together, the MOA studies may help explain the unique results observed with palonosetron in the clinic.

Li:Eisai, Inc: Research Funding. Wu:Eisai: Research Funding. Rojas:Eisai, Inc: Employment. Cantoreggi:Helsinn Healthcare: Employment. Sebastiani:Helsinn Healthcare: Employment. Slusher:Eisai, Inc: Employment.