Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the activation of low-threshold mechanoreceptors. However, the mechanisms behind this inhibition remain unknown. We presently investigated whether stroking the skin reduces the responses of superficial dorsal horn neurons to pruritogens in male C57BL/6J mice. Single-unit recordings revealed that neuronal responses to chloroquine were enhanced during skin stroking, and this was followed by suppression of firing below baseline levels after the termination of stroking. Most of these neurons additionally responded to capsaicin. Stroking did not suppress neuronal responses to capsaicin, indicating state-dependent inhibition. Vesicular glutamate transporter 3 (VGLUT3)-lineage sensory nerves compose a subset of low-threshold mechanoreceptors. Stroking-related inhibition of neuronal responses to chloroquine was diminished by optogenetic inhibition of VGLUT3-lineage sensory nerves in male and female Vglut3-cre/NpHR-EYFP mice. Conversely, in male and female Vglut3-cre/ChR2-EYFP mice, optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited firing responses of spinal neurons to pruritogens after the termination of stimulation. This inhibition was nearly abolished by spinal delivery of the j-opioid receptor antagonist nor-binaltorphimine dihydrochloride, but not the neuropeptide Y receptor Y1 antagonist BMS193885. Optogenetic stimulation of VGLUT3-lineage sensory nerves inhibited pruritogen-evoked scratching without affecting mechanical and thermal pain behaviors. Therefore, VGLUT3-lineage sensory nerves appear to mediate inhibition of itch by tactile stimuli.

Chronic itch (pruritus) is defined as itch lasting longer than six weeks and has an estimated prevalence of 8%-38% worldwide. [1] Although the exact prevalence is difficult to assess, approximately one percent of all outpatient visits per year (~7 million) are considered to be itch-related symptoms in the United States. [2] Acute histaminergic itch can be largely treated, but chronic itch is usually not histaminergic and more difficult to treat. [3] Chronic pruritus may be a symptom of another ailment, such as inflammatory skin, systemic, neurological or psychogenic disease, or it may be the ailment itself. [4] One of the areas in which itch plays a large role is inflammatory skin diseases, such as atopic dermatitis and psoriasis. [3,5] These inflammatory skin disorders are often associated with severe chronic itch, which can lead to an extreme decrease in quality of life. [6-8] Recent findings suggest that neuro-immune interactions are associated with itch initiation and augmentation in inflammatory skin diseases. [9,10] Cytokines are substances that are secreted by the immune system and are thought to regulate inflammatory responses. Interleukins are subtype of cytokines formed by leucocytes and part of the immune regulation system. [11] Current itch research has shown evidence that receptors for the various cytokines such as interleukin (IL)-4, IL-13, IL-31 and IL-33 are expressed on dorsal root ganglion (DRG) neurons and involved in itch in inflammatory skin diseases. [12-15] Understanding the role of the various interleukins and their receptors in the sensory neurons may be a key component of understanding the mechanisms of different itch pathways. IL-23 and Th17 cytokines (eg IL-17A, IL-17F and IL-22) have long been implicated in inflammatory skin diseases due to their roles in inflammation. [6,16] IL-23 is an upstream regulator of Th17 cytokines and is excreted by activated macrophages and dendritic

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