BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release

Abstract

Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8-22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8-22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8-18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine-induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8-22. We show that BAM8-22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8-22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.

Figure 1.

Time course of the mean perceived intensity of itch and nociceptive sensations evoked by spicules containing BAM8–22 or the inactive peptide BAM8–18. A, B, The mean ratings of itch, pricking/stinging, and burning obtained from 15 subjects are plotted for successive intervals of 30 s following spicule application. Starting with the peak rating of each sensory quality, the SEM is plotted every 5 min. The right vertical axis marks the position of three verbal descriptors shown in correspondence with the ratings of mean perceived intensity indicated on the left vertical axis. Inset, The linear regressions for concentration and the logarithmic values of the AUC for itch, pricking/stinging, and burning. Significant slopes were obtained for itch and pricking/stinging but not for burning. Conc, Concentration.

Figure 2.

A–D, Time course of the perceived intensity of itch and nociceptive sensations evoked by spicules containing BAM8–22 (A, C) or histamine (B, D) applied to skin pretreated with an antihistamine (C, D) or a placebo (A, B) in a topical cream. The antihistamine inhibited the sensations evoked by histamine but not by BAM8–22.

Figure 3.

The effects of an antihistamine on the mean areas of dysesthesia, wheal, and flare evoked by spicules containing BAM8–22 or histamine. A–E, The mean areas of alloknesis (A), hyperknesis (B), hyperalgesia (C), wheal (D), and flare (E) evoked by BAM8–22 (BAM) or histamine (Hist) applied to skin pretreated with a topical cream containing placebo (Plac) or an antihistamine (Anti). The number of subjects reporting each effect is in parentheses. The antihistamine prevented or significantly attenuated only the sensory effects of histamine. BAM8–22 produced no wheal or flare. BAM8–18 evoked no dysesthesias, wheal, or flare.