Date Published: June 5, 2019
Publisher: Public Library of Science
Author(s): Victoria Brings Bartsch, Jesse K. Niehaus, Bonnie Taylor-Blake, Mark J. Zylka, Simon Beggs.
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.
Chronic itch (pruritis) and chronic pain can drastically impact daily function, often hindering work performance and severely impairing quality of life [1, 2]. Current treatments do not adequately alleviate symptoms [3, 4] and come with serious side effects . 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 . Pruritogenic compounds released by immune cells activate itch fibers that innervate the skin . While this activation enables recognition of allergens, many pruritis patients suffer from aberrant, unprovoked activity of itch fibers, leading to extreme scratching behavior. Similarly, 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 . Somatosensory neurons are the primary responders to pruritogenic and noxious stimuli, and their dysfunction can cause chronic itch or chronic pain. Characterizing the function of signaling mediators expressed in DRG neurons may reveal candidate molecules to target for the treatment of itch and/or pain.
Here, we sought to determine how Dgki loss in mice affects somatosensory behaviors. Dgki deletion significantly enhanced scratching responses to histamine, but not to other pruritogens. 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. Further, our in vitro calcium imaging experiments showed enhanced response magnitudes in Dgki-/- neurons following histamine exposure. Thus, our data suggest that enhanced responses to histamine in vivo following Dgki deletion is mediated by DRG neurons, though other cells may contribute to this phenotype.