The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivo.
Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.
Rojas
Camilo
C
The Brain Science Institute, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Suite 270, Baltimore, MD 21205, USA.
Li
Ying
Y
Zhang
Jie
J
Stathis
Marigo
M
Alt
Jesse
J
Thomas
Ajit G
AG
Cantoreggi
Sergio
S
Sebastiani
Silvia
S
Pietra
Claudio
C
Slusher
Barbara S
BS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077924:Palonosetron; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis; D044406:Receptors, Serotonin, 5-HT3 / Q000096:biosynthesis; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D013373:Substance P / Q000502:physiology*; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D000932:Antiemetics; D000970:Antineoplastic Agents; D007546:Isoquinolines; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012701:Serotonin; D013373:Substance P; D000077924:Palonosetron; D002945:Cisplatin; D002118:Calcium