Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-α) mRNA expression via histamine H 4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-α impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H 4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H 4 receptor antagonist (JNJ7777120, 10 mg/kg) inhibited the decrease in expression. The effect of the H 4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX 2 receptor antagonist (JNJ10397049, 5 mg/kg) rather than an orexin OX 1 receptor antagonist (SB408124, 30 mg/kg). Although an OX 2 receptor agonist (YNT-185, 20 mg/kg) or a histamine H 3 receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX 2 receptor agonist was antagonized by an H 3 receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H 4 receptor antagonist against cisplatin-induced anorexia.