Temsirolimus is a
prodrug form of
sirolimus (
rapamycin). With its analogs (
everolimus,
ridaforolimus, and
rapamycin), it forms a group of
anticancer agents that block the activity of one of the two mammalian targets of
rapamycin (mTOR) complexes,
mTORC1. We investigated the
emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of
temsirolimus in the least shrew.
Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews
vomiting with maximal efficacy at 10 mg/kg (p < 0.05 and p < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant
emetic effect. We also evaluated the
emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar
emetic profile. Our observational studies indicated that
temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses.
At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg (p < 0.05). We then determined the broad-spectrum
antiemetic potential of a 20 mg/kg (i.p.) dose of
temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D2/3 receptors (
apomorphine and
quinpirole); 2) serotonergic 5-HT3
receptors [5-HT (
serotonin) and 2-methyl-5-HT]; 3)
cholinergic M1 receptors (
pilocarpine and
McN-A-343); 4)
substance P neurokinin NK1 receptors (
GR73632); 5) the L-type
calcium (Ca2+) channel (LTCC) (
FPL64176); 6) the sarcoplasmic endoplasmic reticulum
Ca2+ ATPase inhibitor,
thapsigargin; 7) the
CB1 receptor inverse agonist/antagonist,
SR141716A; and 8) the chemotherapeutic
cisplatin.
Temsirolimus prevented
vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and
antiemetic effects of
temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg
emetic dose of
temsirolimus, whereas its larger
antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising
antiemetic potential of high doses of
temsirolimus and possibly its analogs in least shrews.