Involvement of substance P in the development of cisplatin‐induced acute and delayed pica in rats

Background and Purpose Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin‐induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non‐nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time‐dependent changes in cisplatin‐induced pica and the involvement of SP and NK1 receptors in this behaviour. Experimental Approach Rats were administered cisplatin with or without a daily injection of a 5‐HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin‐induced expression of preprotachykinin‐A (PPT‐A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. Key Results Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2–5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT‐A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. Conclusions and Implications The profiles of cisplatin‐induced pica in rats are similar to clinical findings for cisplatin‐induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin‐induced pica.