Borneol exerts its antipruritic effects by inhibiting TRPA1 and activating TRPM8.

ETHNOPHARMACOLOGICAL RELEVANCE: Borneol is a long-established traditional Chinese medicine that has been found to be effective in treating pain and itchy skin. However, whether borneol has a therapeutic effect on chronic itch and its related mechanisms remain unclear. AIM OF THE STUDY: To investigate the antipruritic effect of borneol and its molecular mechanism. MATERIALS AND METHODS: DrugBAN framework and molecular docking were applied to predict the targets of borneol, and the calcium imaging or patch-clamp recording analysis were used to detect the effects of borneol on TRPA1, TRPM8 or TRPV3 channels in HEK293T cells. In addition, various mouse models of acute itch and chronic itch were established to evaluate the antipruritic effects of borneol on C57BL/6J mice. Then, the borneol-induced pruritic relief was further investigated in Trpa1-/-, Trpm8-/-, or Trpa1-/-/Trpm8-/- mice. The effects of borneol on the activation of TRPM8 and the inhibition of TRPA1 were also measured in dorsal root ganglia neurons of wild-type (WT), Trpm8-/- and Trpv1-/- mice. Lastly, a randomized, double-blind study of adult patients was conducted to evaluate the clinical antipruritic effect of borneol. RESULTS: TRPA1, TRPV3 and TRPM8 are the potential targets of borneol according to the results of DrugBAN algorithm and molecular docking. Calcium imaging and patch-clamp recording analysis demonstrated that borneol activates TRPM8 channel-induced cell excitability and inhibits TRPA1 channel-mediated cell excitability in transfected HEK293T cells. Animal behavior analysis showed that borneol can significantly reduce acute and chronic itch behavior in C57BL/6J mice, but this effect was eliminated in Trpa1-/-, Trpm8-/- mice, or at least in Trpa1-/-/Trpm8-/- mice. Borneol elicits TRPM8 channel induced [Ca2+]i responses but inhibits AITC or SADBE-induced activation of TRPA1 channels in dorsal root ganglia neurons of WT and Trpv1-/- mice, respectively. Furthermore, the clinical results indicated that borneol could reduce itching symptoms in patients and its efficacy is similar to that of menthol. CONCLUSION: Borneol has therapeutic effects on multiple pruritus models in mice and patients with chronic itch, and the mechanism may be through inhibiting TRPA1 and activating TRPM8.

Dictamnine ameliorates chronic itch in DNFB-induced atopic dermatitis mice via inhibiting MrgprA3.

Chronic itch is the most prominent feature of atopic dermatitis (AD), and antihistamine treatment is often less effective in reducing clinical pruritus severity in AD. Multiple studies have shown that histamine-independent itch pathway is thought to predominate in AD-induced chronic itch. Mas-related G-protein-coupled receptor (Mrgpr) A3+ sensory neurons have been identified as one of the major itch-sensing neuron populations, and transient receptor potential (TRP) channel A1 is the key downstream of MrgprA3-mediated histamine-independent itch. MrgprA3-TRPA1 signal pathway is necessary for the development of chronic itch and may be the potentially promising target of chronic itch in AD. Dictamnine is one of the main quinoline alkaloid components of Cortex Dictamni (a traditional Chinese medicine widely used in clinical treatment of skin diseases). However, the anti-inflammatory and anti-pruritic effect of dictamnine on AD have not been reported. In this study, we used the 2,4-dinitrofluorobenzene (DNFB)-induced AD mouse model to observe the scratching behavior, inflammatory manifestations, and to detect the expression of MrgprA3 and TRPA1 in skin and DRG. The data demonstrated that dictamnine effectively inhibited AD-induced chronic itch, inflammation symptoms, epidermal thickening, inflammatory cell infiltration, and downregulated the expression of MrgprA3 and TRPA1. Furthermore, dictamnine restrained the excitability of MrgprA3+ and TRPA1+ neurons. Molecular docking also indicated that dictamnine has better binding affinity with MrgprA3. These results suggest that dictamnine may inhibit chronic itch caused by AD through the MrgprA3-TRPA1 mediated histamine-independent itch pathway, and may have a potential utility in AD treatment.

Electroacupuncture reduces chronic itch via cannabinoid CB1 receptors in the ventrolateral periaqueductal gray.

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at "Quchi" (LI11) and "Hegu" (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.

Psychologic interventions in patients with the chronic dermatologic itch in atopic dermatitis and psoriasis: A step forward with family constellations seminars.

Chronic itch is a complex psychophysiological sensation, which can severely affect the quality of life in patients with atopic dermatitis and psoriasis. Itch depends on the irritation of receptors in the skin and the processing of sensory information in the central nervous system. Severe itch leads to activation and later on to disruption of the stress response, resulting in disorders of skin repair, functional and microstructural changes in the areas of the central nervous system that are responsible for the perception of itch. Psychosocial stress can be an essential factor, activating neurohumoral mechanisms which lead to increased itch and scratch, exacerbating skin damage. Patients with chronic itch often have sleep disorders, increased irritability, and depletion of the nervous system. They are characterized by disrupting social relationships, high incidence of anxiety, depressive disorders, and suicidal tendencies. Psychological methods of intervention can effectively influence various mechanisms in the pathogenesis of itch and scratch and improve social functioning in patients with chronic dermatological itch. In this mini-review, we discuss family constellation seminars as an effective method of psychological intervention that can reduce the intensity of itch, and improve sleep and performance in patients with atopic dermatitis and psoriasis. This method is insufficiently described in previous reviews of psychological interventions in atopic dermatitis and psoriasis patients. The positive impact of family constellations seminars in patients with chronic dermatological itch may be related to reducing stress by improving understanding of the family situation, appropriate management of family secrets, and enhancing interactions with the social environment.

100 Hz Electroacupuncture Alleviated Chronic Itch and GRPR Expression Through Activation of Kappa Opioid Receptors in Spinal Dorsal Horn.

BACKGROUND: Clinical studies have shown that electroacupuncture (EA) alleviates chronic itch. Gastrin-releasing peptide receptor (GRPR) and dynorphin (DYN) in the spinal dorsal horn positively or negatively regulate itch, respectively. However, which frequency of EA is effective on relieving chronic itch and reducing the expression of GRPR, whether DYN-A in the spinal cord is involved in the underlying mechanism of the antipruritus effect of EA remains unknown. METHODS: The mixture of acetone and diethyl ether (1:1) [designated as AEW (acetone/diethyl ether and water) treatment] was used to induce the dry skin model of chronic itch. EA was applied to Quchi (LI11) and Hegu (LI4). Western blot was used to detect the expression of GRPR and DYN-A. Immunofluorescence was used to detect the expression of DYN-A. RESULTS: The AEW administration induced remarkable spontaneous scratching, enhanced the expression of GRPR, and reduced the expression of DYN-A. Compared with the sham EA, 2 Hz EA, or 15 Hz EA group, 100 Hz EA was the most effective frequency for relieving chronic itch, reducing the expression of GRPR, and increasing the expression of DYN-A in the cervical dorsal horn. Furthermore, intraperitoneal injection of kappa opioid receptors (KORs) antagonist nor-Binaltorphimine dihydrochloride (nor-BNI) significantly reversed the effect of 100 Hz EA on the inhibition of both itching behavior and GRPR expression. CONCLUSION: EA at 100 Hz is the most effective frequency that inhibits chronic itch and GRPR expression through activation of KORs in the spinal dorsal horn, which can effectively guide the clinical treatment and improve the antipruritic effect of acupuncture.

Qingpeng Ointment Ameliorates Inflammatory Responses and Dysregulation of Itch-Related Molecules for Its Antipruritic Effects in Experimental Allergic Contact Dermatitis.

The pathogenesis of itchy skin diseases including allergic contact dermatitis (ACD) is complicated and the treatment of chronic itch is a worldwide problem. One traditional Tibetan medicine, Qingpeng ointment (QP), has been used in treatment of ACD in China for years. In this study we used HPLC and LC/MS analysis, combined with a BATMAN-TCM platform, for detailed HPLC fingerprint analysis and network pharmacology of QP, and investigated the anti-inflammatory and antipruritic activities of QP on ACD induced by squaric acid dibutylester (SADBE) in mice. The BATMAN-TCM analysis provided information of effector molecules of the main ingredients of QP, and possible chronic dermatitis-associated molecules and cell signaling pathways by QP. In ACD mice, QP treatment suppressed the scratching behavior induced by SADBE in a dose-dependent manner and inhibited the production of Th1/2 cytokines in serum and spleen. Also, QP treatment reversed the upregulation of mRNAs levels of itch-related genes in the skin (TRPV4, TSLP, GRP, and MrgprA3) and DRGs (TRPV1, TRPA1, GRP, and MrgprA3). Furthermore, QP suppressed the phosphorylation of Erk and p38 in the skin. In all, our work indicated that QP can significantly attenuate the pathological alterations of Th1/2 cytokines and itch-related mediators, and inhibit the phosphorylation of MAPKs to treat the chronic itch.

End-Stage Renal Disease Chronic Itch and Its Management.

End-stage renal disease chronic itch is a frequent symptom that bothers patients with advanced stages of chronic kidney disease. The pathogenesis of the chronic itch symptom is complex and not yet fully understood and includes many metabolic, immunologic, and neurogenic factors. A significant burden of the disease results in decreased quality of life with sleep impairment, depressive symptoms, and increased mortality of affected individuals. No treatment of choice is available; topical therapy (emollients), phototherapy (UV-B), and systemic therapy (antiepileptics, opioid agonists, and antagonists) provide significant relief in varying percentages of patients.