Hemokinin-1-derived peptides have antipruritic effects in rats

Substance P (SP) is a member of the tachykinin peptide family. Hemokinin-1 (HK-1) was recently identified as a new mammalian tachykinin peptide. SP and HK-1 consist of undecapeptides and share a common carboxyl-terminal (C-terminal), Phe-Xaa-Gly-Leu-Met-amide motif, and more varied amino-terminals (N-terminal). The function of SP in the pain system of the spinal cord has been examined in detail, whereas that of HK-1 remains unclear. Therefore, the effects of [Leu]-HK-1 on the induction of scratching behavior by the intrathecal administration of HK-1 or SP and scratching behavior by a subcutaneous injection of histamine and serotonin were examined in order to elucidate the function of HK-1. The pretreatment with [Leu]-HK-1 decreased the induction of scratching behavior by HK-1, but not by SP, while the pretreatment with [Leu]-SP decreased the induction of scratching behavior by SP, but not by HK-1. Furthermore, the pretreatments with [Leu]-HK-1 and [Leu]-SP decreased the frequency of scratching following an intradermal injection of pruritogens, such as serotonin (5-HT) and histamine, into the nape of the neck. The effects of the pretreatment with HK-1 (1-5), an N-terminal fragment peptide, were also examined to determine the function of HK-1. The pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by HK-1 and SP. In addition, the pretreatment with HK-1 (1-5) attenuated the induction of scratching behavior by a subcutaneous injection of histamine and 5-HT, while the pretreatment with SP (1-5) had a negligible effect on the scratching behavior induced by these compounds. Collectively, these results indicated that HK-1 was involved in pruritic processing because the pretreatment with [Leu]-HK-1 and HK-1 (1-5) attenuated the induction of scratching behavior by an injection of histamine and 5-HT. Peptide-derived antagonists, such as [Leu]-HK-1 and HK-1 (1-5), may be unsuitable for the treatment of pruritus because of the difficulties associated with penetrating the blood brain barrier. Therefore, the discovery of chemical compounds that function as antagonists to the HK-1-preferred receptor will become more important in the treatment of pruritic diseases.