Gate control of mechanical itch by a subpopulation of spinal cord interneurons

Abstract

Light mechanical stimulation of the hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors, however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons (INs) that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of the GRP-GRPR signaling pathway. Our studies thereby reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch

Making sense out of spinal cord somatosensory development

“…In particular, such studies have demonstrated that molecular markers can define specific subsets of neurons of a particular sensory modality and that neurons that were previously thought to be similar based on anatomical connectivity can develop from different progenitor domains. For example, a GRPR + subset of the dI5/dIL B lineage is involved in chemical itch sensation and a NPY + subset of the dI4/dIL A lineage is involved in mechanical itch pathways, giving credence to the idea that there are distinct somatosensory submodalities that are integrated via distinct spinal microcircuits (Bourane et al, 2015a;Ma, 2012;Sun et al, 2009). However, neurons that have been defined by anatomical characteristics may arise from more than one developmental population.…”

“…Expression of Lhx1/5 is required for the NPY + fate, while expression of Neurod1/2/6 is required for the dynorphin-expressing (DYN + ) fate (Brohl et al, 2008). The NPY + dI4/dIL A lineage mainly in laminae III-IV has recently been shown to gate itch behaviors, specifically mechanical itch as opposed to chemical-evoked itch (histaminergic and non-histaminergic) (Bourane et al, 2015a) whereas the DYN + fate has been implicated in gating mechanical pain and chemical itch (discussed in the next section).…”

“…TRPM8 (Bautista et al, 2007), TRPV1 (Villeda et al, 2006), MRGPRD (Zylka et al, 2005), SP, CGRP, IB4, TRKA (Snider and McMahon, 1998), VGLUT3 (Seal et al, 2009), TRKB, NPY2R (Li et al, 2011), TRKC, PV (Arber et al, 2000), VGLUT1, Vglut1 (Alvarez et al, 2004;Hantman and Jessell, 2010;Llewellyn-Smith et al, 2007), NK1R, PKCγ (Todd, 2010), Grpr (Sun and Chen, 2007), Som, Dyn (Duan et al, 2014;Xu et al, 2008), LMX1B, RORα, MAFA, LBX1, TLX3, PAX2, GBX1 (Bourane et al, 2015b;Del Barrio et al, 2013;Szabo et al, 2015), Npy (Bourane et al, 2015a). of the direct downstream targets of these TFs that could connect them to terminal differentiation processes such as axon guidance and neurotransmitter or neuropeptide fate (Avraham et al, 2009;Brohl et al, 2008;Cheng et al, 2004Cheng et al, , 2005Hobert, 2011;Pillai et al, 2007).…”

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

“…Recent progress has advanced our understanding of molecular and cellular mechanisms of itch (Ji, 2018; LaMotte et al, 2014; Meixiong and Dong, 2017), including but not limited to the receptors of itch (Alemi et al, 2013; Liu et al, 2009; Liu et al, 2010; Wilson et al, 2013b), the neurotransmitters and neuromodulators of itch (Kardon et al, 2014; Mishra and Hoon, 2013; Sun and Chen, 2007), and especially the itch-mediating neurons and neurocircuits (Bourane et al, 2015; Han et al, 2013; Huang et al, 2018; Mishra and Hoon, 2013; Roberson et al, 2013; Ross et al, 2010; Sun et al, 2017; Sun et al, 2009). Primary sensory neurons especially nociceptors express TRPA1 for pain sensation and sensitization (Bautista et al, 2006; Patapoutian et al, 2009; Story et al, 2003).…”

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

“…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]. des informations sensorielles du toucher léger émanant de la peau velue.…”