Evaluation of itch and pain induced by bovine adrenal medulla (BAM)8-22, a new human model of non-histaminergic itch

Abstract

Chronic itch is a socioeconomic burden with limited management options. Non-histaminergic itch, involved in problematic pathological itch conditions, is transmitted by a subgroup of polymodal C-fibres. Cowhage is traditionally used for studying experimentally induced non-histaminergic itch in humans but encounters some limitations. The present study, therefore, aims to design a new human, experimental model of non-histaminergic itch based on the application of bovine adrenal medulla (BAM)8-22, an endogenous peptide that activates the MrgprX1 receptor. Twenty-two healthy subjects were recruited. Different concentrations (0.5, 1 and 2 mg/ml) of BAM8-22 solution and vehicle, applied by a single skin prick test (SPT), were tested in the first session. In the second session, the BAM8-22 solution (1 mg/ml) was applied by different number of SPTs (1, 5 and 25) and by heat-inactivated cowhage spicules coated with BAM8-22. Provoked itch and pain intensities were monitored for 9 min, followed by the measurement of superficial blood perfusion (SBP) and mechanical and thermal sensitivities. BAM8-22 induced itch at the concentration of 1, 2 mg/ml (p < 0.05) and with the significantly highest intensity when applied through BAM8-22 spicules (p < 0.001). No concomitant pain sensation or increased SBP was observed. SBP increased only in the 25 SPTs area probably due to microtrauma from the multiple skin penetrations. Mechanical and thermal sensitivities were not affected by any of the applications. BAM8-22 applied through heat-inactivated spicules was the most efficient method to induce itch (without pain or changes in SBP and mechanical and thermal sensitivities) suggesting BAM8-22 as a novel non-histaminergic, human, experimental itch model.

Keywords: BAM8-22; cowhage spicules; itch; non-histaminergic itch; pain.

FIGURE 1

Itch induced by BAM8‐22. (A) Peak itch intensity. (B) AUC itch. (C) Temporal profile of itch intensity. (D) Temporal profile of itch intensity, focused on BAM8‐22 2 mg/ml, inactivated spicules and vehicle. Significance indicators: any condition vs. vehicle (*) p < 0.05, (**) p < 0.01, (***) p < 0.001; any condition vs. BAM8‐22 coated spicules (#) p < 0.05, (##) p < 0.01; any condition vs. BAM8‐22 2 mg/ml (¤) p < 0.05, (¤¤) p < 0.01, (¤¤¤) p < 0.001. Vehicle = light blue, BAM8‐22 0.5 mg/ml = light grey, BAM8‐22 1 mg/ml = dark grey, BAM8‐22 2 mg/ml = black, 1 prick = pink, 5 pricks = red, 25 pricks = dark red and inactivated spicules = green. Itch, defined as an unpleasant somatosensation that evokes the desire to scratch, 1 could be considered a minor annoyance often associated with harmless episodic pruritus2,3 caused by minor injuries such as mosquito bites. In its acute form, itch simply prompts a relatively short‐lived scratch response in the affected areas; however, in the last decades, itch started to be considered a disease, especially when it persists for more than 6 weeks becoming chronic. 4 Chronic itch occurs under conditions such as psoriasis, prurigo nodularis, uremic pruritus, drug‐induced itching or atopic dermatitis (AD). 4 Itch interferes with functions such as damag pain were assessed by a modified Visual Analogue Scale (VAS, eVAS Software, Aalborg University, Denmark) installed on a Samsung Note 10.1 Tablet (Samsung, Seoul, South Korea). Subjects were instructed to rate on the two bars (one for itch and one for pain) itch and pain intensities from 0 to 10 continuously throughout the 9‐min sampling (conducte

FIGURE 2

Pain induced by BAM8‐22. (A) Peak pain intensity. (B) AUC pain. (C) Temporal profile of pain intensity. Vehicle = light blue, BAM8‐22 0.5 mg/ml = light grey, BAM8‐22 1 mg/ml = dark grey, BAM8‐22 2 mg/ml = black, 1 prick = pink, 5 pricks = red, 25 pricks = dark red and inactivated spicules = green

FIGURE 3

Superficial blood perfusion and mechanical sensitivity. (A) Mean SBP. (B) Peak SBP. Significance indicators: any condition vs. 25 pricks (•) p < 0.05, (•••) p < 0.001; any condition vs. 5 pricks (+) p < 0.05, (++) p < 0.01, (+++) p < 0.001. Vehicle = light blue, BAM8‐22 0.5 mg/ml = light grey, BAM8‐22 1 mg/ml = dark grey, BAM8‐22 2 mg/ml = black, 1 prick = pink, 5 pricks = red, 25 pricks = dark red and inactivated spicules = green. Values are presented as mean + SEM.