Mouse Model of Touch-Evoked Itch (Alloknesis)

Abstract

Lightly touching normal skin near a site of itch can elicit itch sensation, a phenomenon known as alloknesis. To investigate the neural mechanisms of alloknesis, we have developed an animal model. Low-threshold mechanical stimulation of the skin normally does not elicit any response in naïve C57/BL6 mice. Following acute intradermal (id) injection of histamine in the rostral back, mechanical stimulation 7 mm from the injection site elicited discrete hindlimb scratch bouts directed toward the stimulus. This began at 10 min and peaked 20–40 min post-histamine, declining over the next hour. Histamine itself elicited bouts of scratching not associated with the mechanical stimulus, that ceased after 30 min. Histamine- and touch-evoked scratching was inhibited by the μ-opiate antagonist naltrexone. Touch-evoked scratching was observed following id 5-HT, a PAR-4 agonist and a MrgprC11 agonist BAM8-22, but not chloroquine or a PAR-2 agonist. The histamine H1 receptor antagonist terfenadine prevented scratching and alloknesis evoked by histamine, but not 5-HT, a PAR-4 agonist or a MrgprC11 agonist. In mice with experimental dry skin, there was a time-dependent increase in spontaneous and touch-evoked scratching. This animal model, which to our knowledge is previously unreported, appears to be useful to investigate neural mechanisms of itch and alloknesis.

Pharmacology and Signaling of MAS-Related G Protein–Coupled Receptors

“…Concomitant to the observation that chloroquine-induced scratching behavior is mediated largely by murine MRGPRA3 signaling, intradermal injections of BAM8-22 into the nape of the neck of mice also elicited a profound scratching behavior (Liu et al, 2009). This behavioral result was confirmed by several other studies, the proposed murine MRGPRC agonist "SLIGRL" also elicited itch, and agonist-induced scratching was diminished to ;25% in the MRGPR cluster knockout mouse (see section III.B.1) that lacks MRGPRC (Liu et al, 2009Wilson et al, 2011;Akiyama et al, 2012;Han et al, 2013). However, intradermal injections into the nape of the neck as a secure test for itch were questioned because pain-inducing algogens and pruritogens elicit nearly indistinguishable reactions after this application procedure (Shimada and LaMotte, 2008).…”

“…Intradermal application of chloroquine induced a profound itching behavior at the injection site (Liu et al, 2009). This procedure did not lead to alloknesis, an aberrant sensation of itch when nonitching skin near an itchy skin patch is lightly touched (Akiyama et al, 2012). Chloroquine-induced calcium signals in primary sensory neurons were completely inhibited by removal of extracellular calcium by EGTA and by ;90% after application of ruthenium red, a blocker of transient receptor potential (TRP) cation channels (Liu et al, 2009).…”

“…The latter study is of particular interest because it showed that MRGPRA3/MRGPRC-positive neurons are involved in itch, but not pain perception in mice. Noteworthy, activation of MRGPRC by BAM8-22, but not by "SLIGRL" induced alloknesis in addition to acute itch, which were both independent of histamine signaling (Akiyama et al, 2012). Wilson and coworkers (2011) analyzed downstream effectors involved in MRGPRC-induced itching.…”

Experimental elicitation of itch: Evoking and evaluation techniques

“…Animal models of itch are frequently used in order to investigate roles for chemical substance on histamine-dependent and -independent itch, to analyze the spinal neurotransmission of itch and to find genes involved in the transmission of itch [23,24]. Moreover, animal models of human skin conditions and diseases have been assessed, such as chronic dry skin, alloknesis, and atopic dermatitis [25][26][27]. Recently, evidence for direct communication between keratinocytes and somatosensory nerves via TSLP, a cytokine that plays a part in atopic dermatitis, have been provided, demonstrating that injection of TSLP elicits acute bouts of scratching in mice [7].…”

Estudo dos efeitos de compostos doadores de sulfeto de hidrogênio (H₂S) sobre o prurido agudo induzido pela ativação dos receptores ativados por proteases do tipo 2 (PAR-2) em camundongos.

“…PAR-2 induz coceira diretamente pela ativação do receptor nas fibras nervosas sensoriais que inervam a pele, ou indiretamente pela ativação de queratinócitos ou células do sistema imunológico (mastócitos, neutrófilos e células dendríticas), induzindo a liberação de pruritógenos que ativam as fibras nervosas sensoriais na pele Akiyama et al, 2010c;Akiyama et al, 2012;Steinhoff et al, 2003). Na coceira, PAR-2 também tem um papel na sensibilização periférica: as terminações nervosas sensoriais quando são estimuladas por PAR-2 tornam-se mais sensíveis a vários pruritógenos não histaminérgicos (Akiyama et al, 2012).…”