Cross-sensitization of histamine-independent itch in mouse primary sensory neurons

Abstract

Overexpression of pruritogens and their precursors may contribute to the sensitization of histamine-dependent and –independent itch-signaling pathways in chronic itch. We presently investigated self- and cross-sensitization of scratching behavior elicited by various pruritogens, and their effects on primary sensory neurons. The MrgprC11 agonist BAM8–22 exhibited self- and reciprocal cross-sensitization of scratching evoked by the protease-activated receptor-2 (PAR-2) agonist SLIGRL. The MrgprA3 agonist chloroquine unidirectionally cross-sensitized BAM8–22-evoked scratching. Histamine unidirectionally cross-sensitized scratching evoked by chloroquine and BAM8–22. SLIGRL unidirectionally cross-sensitized scratching evoked by chloroquine. Dorsal root ganglion (DRG) cells responded to various combinations of pruritogens and algogens. Neither chloroquine, BAM8–22 nor histamine had any effect on responses of DRG cell responses to subsequently applied pruritogens, implying that their behavioral self- and cross-sensitization effects are mediated indirectly. SLIGRL unilaterally cross-sensitized responses of DRG cells to chloroquine and BAM8–22, consistent with the behavioral data. These results indicate that unidirectional cross-sensitization of histamine-independent itch-signaling pathways might occur at a peripheral site through PAR-2. PAR-2 expressed in pruriceptive nerve endings is a potential target to reduce sensitization associated with chronic itch.

Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations

“…Most of the GSK101-responsive neurons (79%, 135 of 170), CQ-responsive neurons (83%, 128 of 154), and histamine-responsive neurons (81%, 132 of 163), as defined by the first step in the two-step paired protocol, also responded to capsaicin (Fig. 5, D and E), which is consistent with previous studies (12, 29) and indicates that TRPV1 is broadly distributed in itch-sensing neurons. Furthermore, the data indicated that TRPV4 and TRPV1 activities are present in most sensory neurons that respond to both CQ and histamine.…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…This included substances known to activate Mrgprs, such as chloroquine and BAM8-22 (see section IV), and also histamine and serotonin, at least in juvenile mice . In older animals, the cells become more selective most likely by changes in receptor expression (Akiyama et al, 2012). The itch specificity of these neurons was further validated by an elegant gain-of-function experiment.…”

Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons

“…However, others report separate neural pathways mediating histamine and certain types of non-histamine itch 16,17 . Furthermore, while primary sensory neurons of juvenile mice respond to multiple itch mediators, this non-specificity decreases with age 18 . It remains controversial, therefore, if in the adult there are separate afferents that mediate histamine itch and MrgprA3-dependent non-histamine itch.…”