These results support a mechanistic hypothesis in which frataxin deficiency decreases Nrf2 expression in vivo, causing the sensitivity to oxidative stress in target tissues the DRG and the cerebella, which contributes to the process of neurodegeneration.

Lightly touching normal skin near a site of itch can elicit itch sensation, a phenomenon known as alloknesis. To investigate the neural mechanisms of alloknesis, we have developed an animal model. Low-threshold mechanical stimulation of the skin normally does not elicit any response in naïve C57/BL6 mice. Following acute intradermal (id) injection of histamine in the rostral back, mechanical stimulation 7 mm from the injection site elicited discrete hindlimb scratch bouts directed toward the stimulus. This began at 10 min and peaked 20–40 min post-histamine, declining over the next hour. Histamine itself elicited bouts of scratching not associated with the mechanical stimulus, that ceased after 30 min. Histamine- and touch-evoked scratching was inhibited by the μ-opiate antagonist naltrexone. Touch-evoked scratching was observed following id 5-HT, a PAR-4 agonist and a MrgprC11 agonist BAM8-22, but not chloroquine or a PAR-2 agonist. The histamine H1 receptor antagonist terfenadine prevented scratching and alloknesis evoked by histamine, but not 5-HT, a PAR-4 agonist or a MrgprC11 agonist. In mice with experimental dry skin, there was a time-dependent increase in spontaneous and touch-evoked scratching. This animal model, which to our knowledge is previously unreported, appears to be useful to investigate neural mechanisms of itch and alloknesis.

Several thermo-sensitive TRP channels (TRPV1, -3; TRPA1) have been implicated in itch. In contrast, the role of transient receptor potential vanilloid type-4 (TRPV4) in itch is unknown. Therefore, we investigated if TRPV4, a temperature-sensitive cation channel, plays an important role in acute itch in mice. Four different pruritogens including serotonin (5-hydroxytrytamine, 5-HT), histamine, SLIGRL (PAR2/MrgprC11 agonist) and chloroquine (MrgprA3 agonist) were intradermally injected and itch-related scratching behavior was assessed. TRPV4 knockout (TRPV4KO) mice exhibited significantly fewer 5-HT-evoked scratching bouts compared to wild-type (WT) mice. Notably, no differences between TRPV4KO and WT mice were observed in the number of scratch bouts elicited by SLIGRL and histamine. Pretreatment with a TRPV4 antagonist significantly attenuated 5-HT-evoked scratching in vivo. Using calcium imaging in cultured primary murine dorsal root ganglion (DRG) neurons, the response of neurons after 5-HT application, but not other pruritogens, was significantly lower in TRPV4KO compared to WT mice. A TRPV4 antagonist significantly suppressed 5-HT-evoked responses in DRG cells from WT mice. Approximately 90% of 5-HT-sensitive DRG neurons were immunoreactive for an antibody to TRPV4, as assessed by calcium imaging. These results indicate that serotonin-induced itch is linked to TRPV4.

Chronic itch is a symptom of many skin conditions and systemic disease, and it has been hypothesized that the chronic itch may result from sensitization of itch-signaling pathways. We induced experimental chronic dry skin on the rostral back of mice, and observed a significant increase in spontaneous hindlimb scratches directed to the dry skin. Spontaneous scratching was significantly attenuated by a PAR-2 antibody and 5-HT2A receptor antagonist, indicating activation of these receptors by endogeneous mediators released under dry skin conditions. We also observed a significant increase in the number of scratch bouts evoked by acute intradermal injections of a protease-activated receptor (PAR)-2 agonist and serotonin (5-HT), but not histamine. We additionally investigated if pruritogen-evoked activity of dorsal root ganglion (DRG) neurons is enhanced in this model. DRG cells from dry skin mice exhibited significantly larger responses to the PAR-2 agonist and 5-HT, but not histamine. Spontaneous scratching may reflect ongoing itch, and enhanced pruritogen-evoked scratching may represent hyperknesis (enhanced itch), both potentially due to sensitization of itch-signaling neurons. The correspondence between enhanced behavioral scratching and DRG cell responses suggests that peripheral pruriceptors that respond to proteases and 5-HT, but not histamine, may be sensitized in dry skin itch.