3'-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model.

An itch is a clinical complication that affects millions of patients. However, few treatment options are available. The voltage-gated sodium channel Nav1.7 is predominantly expressed in peripheral sensory neurons and is responsible for the rising phase of action potentials, thereby mediating nociceptive conduction. A gain-of-function mutation of Nav1.7 results in the hyperexcitability of sensory neurons and causes the inherited paroxysmal itch. Conversely, a monoclonal antibody that selectively inhibits Nav1.7 is able to effectively suppress the histamine-dependent itch in mice. Therefore, Nav1.7 inhibitors may possess the potential to relieve the itch. In the present study, using whole-cell voltage-clamp recordings, we demonstrated that 3'-O-methylorobol inhibited Na+ currents in Nav1.7-CHO cells and tetrodotoxin-sensitive Na+ currents in mouse dorsal root ganglion (DRG) neurons with IC50 (half-maximal inhibitory concentration) values of 3.46 and 6.60 µM, respectively. 3'-O-methylorobol also suppressed the tetrodotoxin-resistant Na+ currents in DRG neurons, though with reduced potency (~43% inhibition at 30 µM). 3'-O-methylorobol (10 µM) affected the Nav1.7 by shifting the half-maximal voltage (V1/2) of activation to a depolarizing direction by ~6.76 mV, and it shifted the V1/2 of inactivation to a hyperpolarizing direction by ~16.79 mV. An analysis of 3'-O-methylorobol activity toward an array of itch targets revealed that 3'-O-methylorobol was without effect on histamine H1 receptor, TRPV1, TRPV3, TRPV4, TRPC4 and TRPM8. The intrathecal administration of 3'-O-methylorobol significantly attenuated compound 48/80-induced histamine-dependent spontaneous scratching bouts and the expression level of c-fos in the nuclei of spinal dorsal horn neurons with a comparable efficacy to that of cyproheptadine. Our data illustrated the therapeutic potential for 3'-O-methylorobol for histamine-dependent itching, and the small molecule inhibition of Nav1.7 may represent a useful strategy to develop novel therapeutics for itching.

Current and emerging drugs for the treatment of pruritus: an update of the literature.

INTRODUCTION: Pruritus, particularly in its chronic form, often imposes significant suffering and reductions in patients' quality of life. The pathophysiology of itch is varied depending on disease context, creating opportunities for unique drug development and multimodal therapy. AREAS COVERED: The purpose of this article is to provide an update of the literature regarding current and emerging therapeutics in itch. We review the multitudes of drug targets available and corresponding drugs that have shown efficacy in clinical trials, with a particular emphasis on phase 2 and 3 trials and beyond. Broadly, these targets include therapies directed against type 2 inflammation (i.e. Th2 cytokines, JAK/STAT, lipid mediators, T-cell mediators, and other enzymes and receptors) and neural receptors and targets (i.e. PARs, TRP channels, opioid receptors, MRGPRs, GABA receptors, and cannabinoid receptors). EXPERT OPINION: Therapeutics for itch are emerging at a remarkable pace, and we are entering an era with more and more specialized therapies. Increasingly, these treatments are able to relieve itch beyond their effect on inflammation by directly targeting the neurosensory system.

Suppression of scratching-induced pleasurable sensation by compression nerve blocking and its association with itch relief.

Itch can be suppressed by scratching. At the same time, scratching evokes a pleasurable sensation. In the present study, we investigated the peripheral mechanism of scratching-induced pleasurability and its association with itch relief using compression nerve block. We found that myelinated nerve fibers (Aß-fibers and possibly Aδ-fibers), are involved in transmission of scratching-induced pleasurability. We observed that itch relief effect was the same regardless of whether the pleasurable sensation was evoked by scratching an itch, indicating that pleasure is not a necessary component to induce itch relief. This is the first study to investigate the peripheral mechanism of scratching-induced pleasurability and itch relief.

A transcranial direct current stimulation over the sensorimotor cortex modulates the itch sensation induced by histamine.

OBJECTIVE: Itching can be suppressed by scratching. However, scratching may aggravate itch symptoms by damaging the skin. Therefore, identifying an alternative approach to suppress itching is of clinical importance. The aim of the present study was to determine whether a transcranial direct current stimulation (tDCS) was useful for itch relief. METHODS: The present study was performed on a double-blind, Sham-controlled, and cross-over experimental design. A histamine-induced itch was evoked on the left dorsal forearms of healthy participants, who were asked to report the subjective sensation of itching every 30s for 23 min. tDCS was applied over the sensorimotor cortex (SMC) according to a bi-hemispheric stimulation protocol during the itch stimuli; one electrode was placed over the right SMC, while the other was placed over the left SMC. The peak and lasting sensations of itching were compared between R-A/L-C (anodal electrode placed over the right and cathodal electrode over the left), L-A/R-C (anodal electrode placed over the left and cathodal electrode over the right), and Sham interventions. RESULTS: The peak and lasting itch sensation were significantly suppressed during the R-A/L-C intervention than during the Sham intervention. On the other hand, the L-A/R-C intervention suppressed the peak itch sensation, but the effects did not last for more than a few minutes. CONCLUSIONS: These results suggest that a bi-hemispheric tDCS intervention, especially when the anodal electrode was placed over the SMC of the contralateral side, was a potentially useful method for relieving lasting itch sensations. SIGNIFICANCE: The present study demonstrated that a tDCS intervention may be an alternative approach for suppressing unpleasant itch sensations in healthy participants. Since tDCS has some advantages, namely, its easy application and safety in a clinical setting, it may become a useful method for the treatment of itching.