BACKGROUND:

Itch is one of the most frequent skin complaints and its treatment is challenging. From a neurophysiological perspective, two distinct peripheral and spinothalamic pathways have been described for itch transmission: a histaminergic pathway and a nonhistaminergic pathway mediated by protease-activated receptors (PAR)2 and 4. The nonhistaminergic itch pathway can be activated exogenously by spicules of cowhage, a tropical plant that releases a cysteine protease named mucunain that binds to and activates PAR2 and PAR4.

PURPOSE:

This study was conducted to assess the antipruritic effect of a novel over-the-counter (OTC) steroid-free topical hydrogel formulation, TriCalm(®), in reducing itch intensity and duration, when itch was induced with cowhage, and compared it with two other commonly used OTC anti-itch drugs.

STUDY PARTICIPANTS AND METHODS:

This double-blinded, vehicle-controlled, randomized, crossover study recorded itch intensity and duration in 48 healthy subjects before and after skin treatment with TriCalm hydrogel, 2% diphenhydramine, 1% hydrocortisone, and hydrogel vehicle, used as a vehicle control.

RESULTS:

TriCalm hydrogel significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the two other OTC antipruritic agents and its own vehicle in antipruritic effect. TriCalm hydrogel was eight times more effective than 1% hydrocortisone and almost six times more effective than 2% diphenhydramine in antipruritic action, as evaluated by the reduction of area under the curve.

CONCLUSION:

TriCalm hydrogel has a robust antipruritic effect against nonhistaminergic pruritus induced via the PAR2 pathway, and therefore it could represent a promising treatment option for itch.

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.

The kappa-opioid agonist, nalfurafine, has been approved in Japan for treatment of itch in patients with chronic kidney disease. We presently investigated if systemic administration of nalfurafine inhibited ongoing or touch-evoked scratching behavior (alloknesis) following acuteintradermal injection of histamine or the non-histaminergic itch mediator, chloroquine, in mice. We also investigated if nalfurafine suppressed spontaneous or touch-evoked scratching in an experimental model of chronic dry skin itch. Nalfurafine reduced scratching evoked by histamine and chloroquine. Following acute histamine, but not chloroquine, low-threshold mechanical stimuli reliably elicited directed hindlimb scratchingbehavior, which was significantly attenuated by nalfurafine. In mice with experimental dry skin, nalfurafine abolished spontaneous scratching but had no effect on alloknesis. Nalfurafine thus appears to be a promising treatment for acute itch as well as ongoing itch of dry skin.