Analysis of spinal neurotransmitters in histaminergic and non-histaminergic itch

Abstract

Background: Chronic intractable itch is a profound problem that decreases quality of life and frequently accompanies a variety of inflammatory skin conditions and systemic diseases. The development of antipruritic treatments therefore requires an understanding of the fundamental mechanisms of itch. Objectives: We investigated the roles of substance P (SP), gastrin-releasing peptide (GRP), and glutamate in the spinal neurotransmission of histamine-dependent and -independent itch by using in vivo electrophysiology. Results: In anesthetized mice, responses of single neurons in the superficial dorsal horn to intradermal (i.d.) injection of chloroquine (CQ) were partially reduced by spinal application of the AMPA/kainite antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Co-application of CNQX plus a neurokinin-1 receptor (NK-1R) antagonist produced stronger inhibition, while co-application of CNQX, NK-1R, and GRP receptor (GRPR) antagonists completely inhibited neuronal firing. Neuronal responses elicited by i.d. histamine were abolished by CNQX alone. In behavioral studies, individual intrathecal administration of a GRPR, NK-1, or AMPA antagonist each significantly attenuated CQ-evoked scratching behavior. Co-administration of the NK-1 and AMPA antagonists was more effective, and administration of all 3 antagonists abolished scratching. Intrathecal CNQX alone prevented histamine-evoked scratching behavior. Conclusion: These results suggest that SP, GRP, and glutamate each partially contribute to histamine-independent itch. Meanwhile, histamine-evoked itch is mediated primarily by glutamate. Co-application of NK-1, GRP, and AMPA receptor antagonists may prove beneficial in treating chronic and intractable itch such as atopic dermatitis.