Cisplatin causes over-expression of tachykinin NK1 receptors and increases ERK1/2- and PKA‐ phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem

Abstract: Scant information is available regarding the effects of cisplatin on the expression profile of tachykinin NK1 receptors and downstream signaling during cisplatin-induced emesis. Cisplatin causes peak early- and delayed-phase emesis in the least shrew at 1–2 and 33h post-injection. To investigate the expression profile of NK1 receptor during both emetic phases, we cloned the cDNA corresponding to a ∼700 base pairs of mRNA flanked by two stretches of nucleotides conserved among different species and demonstrated that the shrew NK1 receptor nucleotide sequence shares ∼90% sequence identity with the human NK1 receptor. Of the 12 time-points tested, significant increases in expression levels of NK1 receptor mRNA in the shrew brainstem occurred at 2 and 28h post-cisplatin injection, whereas intestinal NK1 receptor mRNA was increased at 28h. Shrew brainstem and intestinal substance P mRNA levels also tended to increase during the two phases. Furthermore, expression levels of NK1 receptor protein were significantly increased in the brainstem at 2, 8, and 33h post-cisplatin. No change in brainstem 5-HT3 receptor protein expression was observed. The temporal enhancements in NK1 receptor protein expression were mirrored by significant increases in the phosphorylation status of the brainstem ERK1/2 at 2, 8, and 33h post-cisplatin. Phosphorylation of PKA significantly increased at 33rd and 40th hour. Our results indicate associations between cisplatin’s peak immediate- and delayed-phase vomiting frequency with increased: (1) expression levels of NK1 receptor mRNA and its protein level, and (2) downstream NK1 receptor-mediated phosphorylation of ERK1/2 and PKA signaling. [Copyright &y& Elsevier]