Cellular Basis of Itch Sensation

Abstract

Itch and pain are two distinct sensations. Although our previous study suggested that gastrinreleasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord, a long-standing question of whether there are separate neuronal pathways for itch and pain remains unsettled. Here we selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine-dependence. In contrast, pain behaviors were unaffected. Our data also suggest that GRPR + neurons are different from the spinothalamic tract (STT) neurons which have been the focus of the debate. Together, the present study suggests that GRPR + neurons constitute a long-sought labeled line for itch sensation in the spinal cord.Itch has long been considered to be a sub-modality or sub-quality of pain (1-4), because both sensations share many similarities (5). Whether itch and pain, two distinct sensations, are mediated by distinct neural circuits has been the subject of controversy (6-8). In the spinal cord, arguments for the "labeled line" came from electrophysiological recordings in cat showing the presence of a small subset of histamine-responsive, mechanically, thermally and mustard oil insensitive lamina I STT neurons (9). Recent studies in primates, however, found that histamine-sensitive STT neurons were all responsive to noxious mechanical and chemical stimuli, notably capsaicin, arguing against the "labeled line" for itch (10,11). Although our previous data suggested that GRPR is an itch-specific gene in the spinal cord (12), they could not be extrapolated to imply that GRPR + neurons are itch-specific, simply because neurons expressing one sensory modality-specific gene may also express other sensory modalityspecific genes as often seen in sensory neurons (13). One way to address this issue is to selectively ablate a subset of itch-signaling neurons and assess whether pain behaviors are altered in the absence of these neurons. We selectively ablated GRPR + neurons in the spinal cord of mice by intrathecal administration of bombesin-saporin (bombesin-sap), a toxincoupled to bombesin that binds with high affinity to GRPR and results in GRPR internalization and cell death ( fig.S1) (14,15).We first determined the optimal dose and time course of bombesin-sap treatment. Ablation of GRPR + neurons reduced pruritogen-induced scratching behaviors in a dose-dependent manner ( fig. S2). Most of GRPR + neurons (>75%) were lost two weeks after single intrathecal injection of bombesin-sap (400 ng, Fig. 1. A to C). To determine the specificity of bombesin-sap treatment, we analyzed several subpopulations of neurons in the spinal cord by using laminaspecific molecular markers. Expression of neuromedin U receptor 2 (NMUR2) and prodynorphin was not affected in lamina I of mice treated with bombesin-sap ( Fig. 1. D We next examined scratching behaviors of mice treated with bombesin-sap in response to intradermal i...

Un circuit impliqué dans les démangeaisons mécaniques identifié au niveau de la moelle épinière

“…Le circuit des démangeai-sons mécaniques ne dépend donc pas des histamines, conformément à ce qui avait été suggéré chez l'homme [7]. Une population d'interneurones dorsaux exprimant GRPR, le récepteur au GRP (gastrin-releasing peptide), a récemment été identifiée comme intervenant dans le contrôle spinal des déman-geaisons chimiques [8][9][10] (➜). En utilisant un antagoniste de GRPR, ou en éliminant les interneurones GRPR+ qué dans le contrôle des démangeai-sons induites par des stimuli méca-niques légers, non douloureux [5].…”

Molecular Mechanisms of Itch and Pain: An Overview

“…In this study, both GRPR deletion and pharmacological inhibition significantly attenuated the scratch response against various pruritogen stimuli. In addition, ablation of GRPR-expressing neurons in the spinal cord almost completely abolished the scratch response against histaminergic as well as non-histaminergic pruritogens (CQ, PAR2 agonist, endothelin-1) [36] . Based on these studies, it has been argued that GRPR-positive dorsal horn neurons are itch-transmitting, second-order neurons.…”

“…As for synaptic transmission by the itch-specific sensory neurons, gastrin-releasing peptide (GRP) was suggested as an itch-transmitting neurotransmitter [35,36] . In this study, GRP was expressed in sensory neurons, while the GRP receptor (GRPR) was expressed in dorsal horn neurons.…”

Mechanisms Regulating Epidermal Innervation in Pruritus of Atopic Dermatitis

“…However, using gastrin-releasing peptide receptor (GRPR)-mutant mice or saporin-conjugating bombesin, the GRP/GRPR system was shown to be involved specifically in itch perception via the spinal cord (Sun and Chen, 2007;Sun et al, 2009). Recently, GRP + fibers were histologically shown to be present in mouse skin, with the percentage of PGP9.5 + fibers that are GRP + being exceptionally high only in the epidermis of NC/Nga mice with AD ( Figure 10) (Tominaga et al, 2009b).…”