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Cav3.2 T-type calcium channels are important mediators of nociceptive signaling, but their roles in the transmission of itch remains poorly understood. Here we report a key involvement of these channels as key modulators of itch/pruritus-related behavior. We compared scratching behavior responses between wild type and Cav3.2 null mice in models of histamine- or chloroquine-induced itch. We also evaluated the effect of the T-type calcium channel blocker DX332 in male and female wild-type mice injected with either histamine or chloroquine. Cav3.2 null mice exhibited decreased scratching responses during both histamine- and chloroquine-induced acute itch. DX332 co-injected with the pruritogens inhibited scratching responses of male and female mice treated with either histamine or chloroquine. Altogether, our data provide strong evidence that Cav3.2 T-type channels exert an important role in modulating histamine-dependent and -independent itch transmission in the primary sensory afferent pathway, and highlight these channels as potential pharmacological targets to treat pruritus.
Learn More >Voltage-gated sodium channel Nav1.7 has been validated as a perspective target for selective inhibitors with analgesic and anti-itch activity. The objective of this study was to discover new candidate compounds with Nav1.7 inhibitor properties. The authors hypothesized that their approach would yield at least one new compound that inhibits sodium currents in vitro and exerts analgesic and anti-itch effects in mice.
Learn More >The discovery of MRGPRX2 marks an important change in MC biology, explaining non-IgE-mediated clinical phenomena relying on MCs. As receptor for multiple drugs, MRGPRX2 is crucial to drug-induced hypersensitivity. However, not only drugs, but also endogenous mediators like neuropeptides and host defense peptides activate MRGPRX2, suggesting its broad impact in cutaneous pathophysiology. Here, we give a brief overview of MRGPRX2 and its regulation by microenvironmental stimuli, which support MCs and can be altered in skin disorders, and briefly touch on the functional programs elicited by MRGPRX2 ligation. Studies in Mrgprb2-deficient mice (the murine ortholog) help illuminate MRGPRX2's function in health and disease. Recent advances in this model support the long-suspected operational unit between MCs and nerves, with MRGPRX2 being a vital component. Based on the limited evidence for a major contribution of FcεRI/IgE-activated MCs to atopic dermatitis (AD), we develop the hypothesis that MRGPRX2 constitutes the missing link connecting MCs and AD, at least in selected endotypes. Support comes from the multifold changes in the MC-neuronal system of AD skin (e.g. greater density of MCs and closer connections between MCs and nerves, increased PAR-2/Substance P). We theorize that these deregulations suffice to initiate AD, but external triggers, many of which activating MRGPRX2 themselves (e.g. Staphylococcus aureus) further feed into the loop. Itch, the most burdensome hallmark of AD, is mostly non-histaminergic but tryptase-dependent, and tryptase is preferentially released upon MRGPRX2 activation. Because MRGPRX2 is a very active research field, some of the existing gaps are likely to be closed soon.
Learn More >PUVA (psoralen UVA) therapy is used to treat a variety of skin conditions, such as vitiligo psoriasis, eczema and mycosis fungoides, but it is frequently accompanied by phototoxicity leading to burning pain, itch and erythema. Clinically used psoralen derivatives 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen at physiologically relevant concentrations were able to activate and photosensitize two recombinant thermoTRP (temperature-gated Transient Receptor Potential) ion channels, TRPA1 (Transient Receptor Potential Ankyrin type 1) and TRPV1 (Transient Receptor Potential Vanilloid type 1), which are known to be involved in pain and itch signaling. 8-MOP enhanced reactive oxygen species (ROS) production by UVA light, and the effect of 8-MOP on TRPA1 could be abolished by the antioxidant N-acetyl cysteine and by removal of critical cysteine residues from the N-terminus domain of the channel. Natively expressed mouse TRPA1 and TRPV1 both contribute to photosensitization of cultured primary afferent neurons by 8-MOP, while direct neuronal activation by this psoralen-derivative is mainly dependent on TRPV1. Both TRPA1 and TRPV1 are to a large extent involved in controlling 8-MOP-induced neuropeptide release from mouse trachea. Taken together our results provide a better understanding of the phototoxicity reported by PUVA patients and indicate a possible therapeutic approach to alleviate the adverse effects associated with this therapy.
Learn More >Chronic pruritus is one of the main symptoms in dermatology. We investigated a new intervention for chronic pruritus by neurostimulation through matrix electrodes. In this randomized controlled trial, 29 patients with chronic pruritus caused by a variety of dermatological diseases were allocated to an experimental group (EG; n = 14, 4-Hz neurostimulation of the itching area through matrix electrodes) or the control group (CG; n = 15, placement of matrix electrodes without neurostimulation). Outcome measures were the itching sensation as measured by a Numerical Rating Scale immediately after the intervention and the intermediate effect measured by the average itching sensation on the day before the intervention compared with the average itching sensation on day 1, 2 and 3 after the intervention. Regarding the short-term effect on itching, the anova showed a significant interaction effect for the 5-min stimulation with a larger reduction in the EG with a large effect size of d = 1.10. The average reduction in itching intensity was 78.2% for the EG compared with 34.3% for the CG. For the intermediate effect, no significant interaction was found (F = 1.721, P = 0.199). Comparing the itching sensation at day 0 with day 3, the interaction effect showed a statistical trend toward a greater reduction in the EG (F = 3.178, P = 0.086; statistical trend, d = 0.69). This study proved that neurostimulation through matrix electrodes is effective in the short-term reduction of itching in patients with chronic pruritus caused by dermatological diseases. Additional studies are needed with larger patient pools and covering longer study periods.
Learn More >In this issue of Immunity, Xu et al. reveal that dermal dendritic cells produce interleukin-31, which acts on neurons to promote wound itch. Their findings link itch associated with deeper wounds-wounds that extend beyond the epithelium-to the cells and cytokines that mediate wound healing.
Learn More >Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermal-epidermal junction (DEJ). Itch (pruritus) is one of the commonest symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimised treatments for people with EB and improving quality of life. This review summarises current evidence on the prevalence, mechanisms and management of itch in EB.
Learn More >A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G activator with minimal β-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates.
Learn More >Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor STAT3 and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Learn More >An accelerating basic science literature is providing key insights into the mechanisms by which spinal neuropeptide Y (NPY) inhibits chronic pain. A key target of pain inhibition is the G-coupled neuropeptide Y1 receptor (Y1). Y1 is located in key sites of pain transmission, including the peptidergic subpopulation of primary afferent neurons and a dense subpopulation of small, excitatory, glutamatergic/somatostatinergic interneurons (Y1-INs) that are densely expressed in the dorsal horn, particularly in superficial lamina I-II. Selective ablation of spinal Y1-INs with an NPY-conjugated saporin neurotoxin attenuates the development of peripheral nerve injury-induced mechanical and cold hypersensitivity. Conversely, conditional knockdown of NPY expression or intrathecal administration of Y1 antagonists reinstates hypersensitivity in models of chronic latent pain sensitization. These and other results indicate that spinal NPY release and the consequent inhibition of pain facilitatory Y1-INs represent an important mechanism of endogenous analgesia. This mechanism can be mimicked with exogenous pharmacological approaches (e.g. intrathecal administration of Y1 agonists) to inhibit mechanical and thermal hypersensitivity and spinal neuron activity in rodent models of neuropathic, inflammatory, and postoperative pain. Pharmacological activation of Y1 also inhibits mechanical- and histamine-induced itch. These immunohistochemical, pharmacological, and cell type-directed lesioning data, in combination with recent transcriptomic findings, point to Y1-INs as a promising therapeutic target for the development of spinally directed NPY-Y1 agonists to treat both chronic pain and itch.
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