Abstract
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.
Highlights
An itch is an unpleasant sensation that induces the urge to seek out the source and scratch [1]
Substantial evidence has demonstrated that the capsaicin-activated ion channel TRPV1 and the cold-activated ion channel TRPM8 in peripheral neurons, as well as the transient receptor potential (TRP) cation channels TRPV3 and TRPV4 in epidermal keratinocytes, are the key regulators of histaminergic itching [7,8,9,10]
We demonstrated that 3’-O-methylorobol potently inhibited Nav1.7 and tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (VGSC) currents in mice dorsal root ganglion (DRG) neurons with a much weaker effect on tetrodotoxin-resistant (TTX-R) Na+ currents. 3’-O-methylorobol showed no effect against an array of itch targets including the H1 receptor, TRPV1, TRPV3, TRPV4, TRPC4 and TRPM8
Summary
An itch is an unpleasant sensation that induces the urge to seek out the source and scratch [1]. The pharmacological inhibition of TRPV1, TRPV3, TRPV4 or TRPM8 has been shown to effectively reduced scratching behavior in the mouse models of the histaminergic itch [8,10,11,12,13] These findings indicate that ion channels are important targets in itch management. It was reported that the pharmacological blockade of Nav1.7 reduced itching induced by methylglyoxal or in streptozotocin-induced diabetic mice, indicating that Nav1.7 played a key role in itching in a mouse model of type 1 diabetes [18] All of these significant findings suggest that Nav1.7 is a novel and promising target for itch management. Our research indicates that 3’-O-methylorobol may be a useful lead compound for the development of novel antipruritics
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