Enhanced histamine-induced itch in diacylglycerol kinase iota knockout mice.

Victoria Brings Bartsch,Bonnie Taylor-Blake,Jesse K Niehaus,Mark J Zylka

doi:10.1371/journal.pone.0217819

Abstract

Subsets of small-diameter dorsal root ganglia (DRG) neurons detect pruritogenic (itch-causing) and algogenic (pain-causing) stimuli and can be activated or sensitized by chemical mediators. Many of these chemical mediators activate receptors that are coupled to lipid hydrolysis and diacylglycerol (DAG) production. Diacylglycerol kinase iota (DGKI) can phosphorylate DAG and is expressed at high levels in small-diameter mouse DRG neurons. Given the importance of these neurons in sensing pruritogenic and algogenic chemicals, we sought to determine if loss of DGKI impaired responses to itch- or pain-producing stimuli. Using male and female Dgki-knockout mice, we found that in vivo sensitivity to histamine—but not other pruritogens—was enhanced. In contrast, baseline pain sensitivity and pain sensitization following inflammatory or neuropathic injury were equivalent between wild type and Dgki-/- mice. In vitro calcium responses in DRG neurons to histamine was enhanced, while responses to algogenic ligands were unaffected by Dgki deletion. These data suggest Dgki regulates sensory neuron and behavioral responses to histamine, without affecting responses to other pruritogenic or algogenic agents.

Highlights

Chronic itch and chronic pain can drastically impact daily function, often hindering work performance and severely impairing quality of life [1, 2]
Whereas others have examined the role of DGK iota (Dgki) in the brain, no one has yet looked at the function of Dgki in the dorsal root ganglia (DRG), which is the neuronal tissue in which Dgki is most highly expressed in mice (Table 1) [41]
The effect of Dgki loss on somatosensory behavior was specific to histamine-induced itch, as there were no alterations in baseline pain or pain sensitization in these animals

Summary

Introduction

Chronic itch (pruritis) and chronic pain can drastically impact daily function, often hindering work performance and severely impairing quality of life [1, 2]. Itch- and pain-sensing neurons, whose cell bodies lie in the dorsal root ganglia (DRG), respond to pruritogenic and noxious stimuli in the periphery and transduce these signals to the central nervous system for sensory processing [4]. Pruritogenic compounds released by immune cells activate itch fibers that innervate the skin [6]. While this activation enables recognition of allergens, many pruritis patients suffer from aberrant, unprovoked activity of itch fibers, leading to extreme scratching behavior. Algogenic compounds released following injury to nerves or tissues throughout the body can activate and sensitize peripheral pain fibers, shifting patients toward a state of pain hypersensitivity that can persist after the injury has healed [7]. Somatosensory neurons are the primary responders to pruritogenic and noxious stimuli, and their dysfunction

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Conclusion