Preprotachykinin‐A mRNA changes in response to cisplatin‐induced emesis in the least shrew

Abstract

Cisplatin (CIS) and related drugs cause vomiting in cancer patients. We used the least shrew (Cryptotis parva) emesis model to study this effect, as our previous work has shown that CIS‐treated shrews mimic the biphasic vomiting pattern seen in humans. The acute phase, due presumably to gut and/or medullary serotonin release, occurs within hours. The delayed phase, due presumably to medullary release of substance P (SP), occurs after an emesis‐free period of one (shrews) to several days (humans). We studied the role of SP in CIS‐induced emesis by injecting least shrews with 10 mg/kg CIS (i.p.) and measuring changes in mRNA levels of preprotachykinin‐A (PPTA), the precursor for SP. At different post‐CIS times, tissues from CIS or control shrews were collected and processed for quantitative PCR (QPCR). Whole brain tissue showed a modest increase in PPTA up to 3.5h, a 3 to 14‐fold increase until 33h, then a return to control levels. QPCR of gut tissue showed a rapid rise to 6h, followed by a decrease to below control levels. At 20h, it increased gradually until 33h, then fell below the basal level. Overall, brain PPTA was constantly up‐regulated for 33h, while gut PPTA was upregulated biphasically, coincident with the emetic phases. Thus, SP production in both brain and gut is coordinated with, and may play a role in the modulation of, both phases of CIS‐induced emesis. This study was supported by NIH grant #R01CA115331 to Dr. Darmani.