ABSTRACT
BACKGROUND: Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in peripheral sensory neurons and serve as sensors for various irritants. METHODS: We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from wild-type, TRPA1(-/-) and TRPV1(-/-) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection model was employed to assess econazole-induced itch and pain in vivo. RESULTS: Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker. Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(-/-) mouse DRG neurons but was not significant in the TRPV1(-/-) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole. Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole induced itch and pain in wild-type mice, with reduced responses in TRPA1(-/-) mice. CONCLUSIONS: These findings suggested that the imidazole derivatives econazole and miconazole may induce skin irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the adverse effects of econazole.
Subject(s)
Antifungal Agents , Calcium , Econazole , Ganglia, Spinal , Sensory Receptor Cells , TRPA1 Cation Channel , TRPV Cation Channels , Transient Receptor Potential Channels , Animals , Econazole/pharmacology , TRPA1 Cation Channel/metabolism , TRPA1 Cation Channel/genetics , Antifungal Agents/toxicity , Antifungal Agents/pharmacology , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/cytology , Humans , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Transient Receptor Potential Channels/metabolism , Transient Receptor Potential Channels/genetics , HEK293 Cells , Calcium/metabolism , TRPV Cation Channels/metabolism , TRPV Cation Channels/genetics , Mice , Male , Mice, Knockout , Mice, Inbred C57BL , Pruritus/chemically induced , Pain/drug therapyABSTRACT
Uremic pruritus, a severe complication in patients with chronic kidney disease, is associated with a high prevalence. It can cause depression and sleep disorders, and seriously affect the quality of life and the social relations of patients. Recently, there is growing evidence showing that κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, can effectively and safely reduce itching symptoms in patients with refractory uremic pruritus. Herein, we reviewed the epidemiology, pathogenesis, clinical symptoms, and treatment strategies of uremic pruritus, and summarized in detail the progress in clinical research on the use of κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, in the management of patients with uremic pruritus.
Subject(s)
Morphinans , Pruritus , Receptors, Opioid, kappa , Spiro Compounds , Uremia , Humans , Receptors, Opioid, kappa/agonists , Pruritus/etiology , Pruritus/drug therapy , Morphinans/therapeutic use , Uremia/complications , Uremia/etiology , Spiro Compounds/therapeutic use , Nalbuphine/therapeutic use , Renal Insufficiency, Chronic/complicationsABSTRACT
Anhedonia, the reduced ability to experience pleasure, is a prevalent symptom in various psychiatric disorders, but has not been investigated in dermatological conditions, particularly those characterized by chronic itch. This study aimed to examine the prevalence and clinical correlates of anhedonia in patients with chronic itch. A cross-sectional study was conducted in 137 patients with chronic itch, classified according to the International Forum for the Study of Itch (IFSI) classification. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS) and Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS). Itch severity, quality of life, and psychological distress were assessed using the Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), ItchyQoL, and Hospital Anxiety and Depression Scale (HADS), respectively. The mean SHAPS score was 1.0 ± 1.7 points, and the mean ACIPS total score was 76.9 ± 16.2 points. In the study sample, 13.1% of patients were identified as anhedonic, with a higher prevalence observed in those with severe and very severe itch. Anhedonia was significantly correlated with itch severity (R = 0.2, p=0.02 for 24 h VASmean and SHAPS; R = 0.2, p = 0.01 for 24 h VASmax and SHAPS), anxiety symptoms (R = 0.3, p < 0.001 for SHAPS and HADS-anxiety), depression symptoms (R = 0.4, p < 0.001 for SHAPS and HADS-depression), and impairment in quality of life (R = 0.2, p = 0.014 for SHAPS and ItchyQoL). Anhedonia is a significant and prevalent aspect of psychological distress in patients with chronic itch. Addressing this symptom may not only improve patients' overall mental health but also enhance the effectiveness of treatments for chronic itch. Future research is needed to elucidate further the mechanisms underlying the relationship between anhedonia and chronic itch and to develop targeted interventions for this population.
Subject(s)
Anhedonia , Pleasure , Pruritus , Quality of Life , Severity of Illness Index , Humans , Pruritus/psychology , Pruritus/diagnosis , Pruritus/epidemiology , Female , Male , Middle Aged , Cross-Sectional Studies , Chronic Disease , Adult , Aged , Prevalence , Psychological DistressSubject(s)
Back , Neck , Pruritus , Humans , Neck/pathology , Pruritus/etiology , Pruritus/diagnosis , Exanthema/diagnosis , Exanthema/etiology , Exanthema/pathology , Male , Female , Diagnosis, DifferentialABSTRACT
Diospyros lotus has been traditionally used in Asia for medicinal purposes, exhibiting a broad spectrum of pharmacological effects including antioxidant, neuroprotective and antiinflammatory properties. While the antiitch effect of D. lotus leaves has been reported, studies on the detailed mechanism of action in microglia and astrocytes, which are members of the central nervous system, have yet to be revealed. The present study aimed to investigate effects of D. lotus leaf extract (DLE) and its main component myricitrin (MC) on itchrelated cytokines and signaling pathways in lipopolysaccharide (LPS)stimulated microglia. The effect of DLE and MC on activation of astrocyte stimulated by microglia was also examined. Cytokine production was evaluated through reverse transcription PCR and western blot analysis. Signaling pathway was analyzed by performing western blotting and immunofluorescence staining. The effect of microglia on astrocytes activation was evaluated via western blotting for receptors, signaling molecules and itch mediators and confirmed through gene silencing using short interfering RNA. DLE and MC suppressed the production of itchrelated cytokine IL6 and IL31 in LPSstimulated microglia. These inhibitory effects were mediated through the blockade of NFκB, MAPK and JAK/STAT pathways. In astrocytes, stimulation by microglia promoted the expression of itchrelated molecules such as oncostatin M receptor, interleukin 31 receptor a, inositol 1,4,5trisphosphate receptor 1, lipocalin2 (LCN2), STAT3 and glial fibrillary acidic protein. However, DLE and MC significantly inhibited these receptors. Additionally, astrocytes stimulated by microglia with IL6, IL31, or both genes silenced did not show activation of LCN2 or STAT3. The findings of the present study demonstrated that DLE and MC could suppress pruritic activity in astrocytes induced by microgliaderived IL6 and IL31. This suggested the potential of DLE and MC as functional materials capable of alleviating pruritus.
Subject(s)
Astrocytes , Diospyros , Flavonoids , Interleukin-6 , Microglia , Plant Extracts , Plant Leaves , Pruritus , Astrocytes/drug effects , Astrocytes/metabolism , Microglia/drug effects , Microglia/metabolism , Plant Extracts/pharmacology , Plant Extracts/chemistry , Animals , Flavonoids/pharmacology , Flavonoids/chemistry , Mice , Interleukin-6/metabolism , Interleukin-6/genetics , Plant Leaves/chemistry , Pruritus/drug therapy , Pruritus/metabolism , Diospyros/chemistry , Lipopolysaccharides , Signal Transduction/drug effects , Inflammation/metabolism , Inflammation/drug therapy , InterleukinsABSTRACT
Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering disorder. Diagnosis always relies on skin pathology and direct immunofluorescence (DIF), with typical linear deposits of IgA along the basement membrane zone (BMZ). The typical clinical manifestation is tense bullae arranged like the "string of pearls" companied with severe pruritus. Dapsone is often considered first-line therapy for LABD, and it is necessary to test the HLA-B*1301 gene to prevent the occurrence of dapsone-induced hypersensitivity syndrome (DHS). Here we report a case of LABD resistant to corticosteroid and sulfasalazine, while waiting for HLA-B*1301 gene test results, dupilumab was used to control severe pruritus.
Subject(s)
Antibodies, Monoclonal, Humanized , Linear IgA Bullous Dermatosis , Pruritus , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Linear IgA Bullous Dermatosis/drug therapy , Linear IgA Bullous Dermatosis/diagnosis , Pruritus/drug therapy , Pruritus/etiology , Pruritus/immunology , Male , Treatment Outcome , Female , Adult , Middle Aged , Skin/pathologyABSTRACT
Itching is a prominent clinical manifestation of sensitive skin; it reduces cutaneous barrier function, mainly caused by dryness. Scratching to relieve itching destroys the skin barrier, thus forming the itch-scratch cycle that results in additional disruption of skin barrier and chronic itching. Treatment involves alleviation from itching for sensitive skin. Recently, substance P (11-amino acid neuropeptide of the tachykinin family) and neurokinin 1 receptor (NK1R) have been considered to provide a key pathway to treat chronic itching. A single-center, open-label study was conducted comprising subjects with dry, itchy, and sensitive skin to evaluate the efficacy of two types of itch-relief moisturizers, mist and lotion, containing maltotetraose (MTO). In all, 35 subjects used mist containing MTO, resulting in significant improvement in itch score from 1 minute to 2 hours following single application. On the other hand, 34 subjects applied lotion containing MTO for 1 week, resulting in significant improvement in itch score, skin hydration, and clinical scores of erythema/redness and dryness; however, in both cases, improve-ment was not observed in the measurement of transepidermal water loss (TEWL). It was concluded that two types of itch-relief moisturizers containing MTO were effective for dry, itchy, and sensitive skin.
Subject(s)
Pruritus , Humans , Pruritus/drug therapy , Pruritus/etiology , Female , Male , Adult , Middle Aged , Skin Cream/administration & dosage , Emollients/administration & dosage , Emollients/therapeutic use , Young Adult , Aged , Treatment Outcome , Water Loss, Insensible/drug effects , Oligosaccharides/administration & dosage , Administration, CutaneousABSTRACT
The pattern of itching in patients with atopic dermatitis has not been systematically studied. Therefore, this study aimed to assess the pattern of itching in adults with atopic dermatitis using questionnaires to assess for a circadian rhythm of itching in participating patients at a single institution (n = 241). A self-report questionnaire was used to assess circadian rhythm and intensity of itching in patients. In addition, the patients' disease severity (Eczema Area and Severity Index [EASI]) and quality of life (Dermatology Life Quality Index [DLQI]) were assessed. Itching occurred most frequently (74.69%) and with the greatest severity (62.66%) between 20:00 and 00:00, and the least number of patients (25.31%) experienced itching between 04:00 and 08:00. The DLQI and EASI scores both correlated with the average and maximum itch intensity (r = 0.582, r = 0.533, respectively; r = 0.539, r = 0.517, respectively; p < 0.001). The DLQI and EASI scores were associated with average itch intensity (B = 0.179, B = 0.204, respectively; 95% CI: 0.112 to 0.246, 95% CI: 0.096 to 0.313, respectively; p < 0.001), and the EASI score was associated with males and family history (B = 0.285, B = 0.287, respectively; 95% CI: 0.094 to 0.476, 95% CI: 0.096 to 0.478, respectively; p = 0.003). Adult patients with atopic dermatitis exhibited a circadian rhythm of itching; these study results could positively impact treatment approaches.
Subject(s)
Circadian Rhythm , Dermatitis, Atopic , Pruritus , Quality of Life , Severity of Illness Index , Humans , Dermatitis, Atopic/physiopathology , Dermatitis, Atopic/complications , Dermatitis, Atopic/diagnosis , Pruritus/physiopathology , Pruritus/etiology , Pruritus/diagnosis , Male , Female , Adult , Cross-Sectional Studies , Middle Aged , Young Adult , Time Factors , Surveys and Questionnaires , Self Report , Aged , AdolescentABSTRACT
Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re â LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re â LS â LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.
Subject(s)
Anxiety , GABAergic Neurons , Hypothalamic Area, Lateral , Pruritus , Animals , Mice , GABAergic Neurons/metabolism , Chronic Disease , Disease Models, Animal , Midline Thalamic Nuclei/metabolism , Male , Behavior, Animal , Neural Pathways , Neuronal Plasticity , Septal NucleiABSTRACT
GENERAL PURPOSE: To present current evidence regarding the physiology, assessment, and management of wound itch. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Summarize current understanding of itch physiology.2. Apply current evidence to the management of wound itch.
Itch is a symptom that can be experienced by persons with open wounds. Whereas advances are being made in the understanding and management of itch, the molecular and cellular physiology of itch is still not fully understood. To summarize recent literature to determine what developments have been made in terms of the physiology, assessment, and management of wound itch. The literature was searched in PubMed and CINAHL Complete databases, limited to the last 5 years and articles in English. Articles were selected based on reference to wound-related itch. The chosen articles and their references were thoroughly reviewed. Additional relevant studies were found in database alerts including Google Scholar and JAMA Online First: Medical News and in searching reference lists of associated articles. In addition to article author, title, and year of publication, extracted data included article type, purpose, results, recommendations, and limitations. Findings related to wound-related itch, postburn itch, venous ulcers, itch physiology, itch assessment, and itch interventions are described. The consensus is that wound-related itch is underevaluated and undertreated. The physiology of itch is not completely understood, and the effectiveness of treatments for wound itch is not known. Further studies with larger samples need to be undertaken to increase the understanding of wound-related itch; its etiology, physiology, and assessment; and treatment effectiveness.
Subject(s)
Pruritus , Humans , Pruritus/physiopathology , Pruritus/etiology , Pruritus/therapy , Wounds and Injuries/therapy , Wounds and Injuries/complications , Wound Healing/physiologyABSTRACT
OBJECTIVE: To evaluate the effectiveness and feasibility of combined treatment with compound fluocinolone acetonide cream and guaiazulene in patients with neurodermatitis. METHODS: A prospective study was conducted on 92 outpatient patients diagnosed with neurodermatitis at our dermatology department from January 2022 to December 2023. Using a random number table, these patients were evenly divided into a control group and an experimental group, with 46 individuals in each group. The control group received treatment with compound fluocinolone acetonide alone, while the experimental group additionally received oral guaiazulene tablets. Clinical symptom and sign scores, Visual Analog Scale (VAS) scores, skin lesion itching scores, comprehensive efficacy, treatment onset time, adverse reactions, and quality of life were monitored, recorded, and compared. RESULTS: In the 2-week treatment period, patients in the experimental group showed significant improvement in skin symptoms and signs, with scores significantly lower than those in the control group (P < 0.05). After treatment, VAS and skin lesion itching scores in the experimental group were significantly reduced (P < 0.05), demonstrating a more pronounced therapeutic advantage compared to the control group (P < 0.05). Although the effective rate in the experimental group was as high as 86.96%, there was no significant advantage compared to the control group, and the difference in treatment efficacy was not significant (P > 0.05). The treatment onset time in the experimental group was significantly shorter than that in the control group (P < 0.05), and the incidence of adverse reactions was lower (P < 0.05). The quality of life in the experimental group improved significantly after treatment, with DLQI scores lower than those in the control group (P < 0.05). CONCLUSION: Combined treatment with compound fluocinolone acetonide cream and guaiazulene demonstrates excellent efficacy and feasibility in the management of neurodermatitis. Compared to standard treatment alone, it yields superior clinical outcomes.
Subject(s)
Feasibility Studies , Fluocinolone Acetonide , Quality of Life , Skin Cream , Humans , Fluocinolone Acetonide/administration & dosage , Fluocinolone Acetonide/adverse effects , Female , Male , Middle Aged , Adult , Prospective Studies , Treatment Outcome , Skin Cream/administration & dosage , Sesquiterpenes, Guaiane/administration & dosage , Drug Therapy, Combination/methods , Pruritus/drug therapy , Pruritus/diagnosis , Aged , Administration, Oral , AzulenesABSTRACT
Pruritus is a common complaint in dermatology outpatient clinics. It is defined as chronic pruritus if the symptoms last 6 weeks or longer. Fibromyalgia is a chronic, extensive pain syndrome that is well-known for its clinical signs, such as exhaustion, sleeping disorders, and some other pain symptoms. In the present study, it was investigated whether chronic pruritus patients were accompanied by fibromyalgia. The study included 100 patients with chronic pruritus and 100 controls without dermatological disease. All of the individuals were first evaluated in the dermatology clinic, and the patients having any musculoskeletal symptoms were then referred to a physiatrist in terms of accompanying fibromyalgia syndrome. Fibromyalgia was detected in 29 (29%) of 100 chronic pruritus patients and 6 (6%) of 100 patients in the control group. There was a statistically significant difference between the two groups regarding accompanying FM (p < 0.001). In the chronic pruritus group, pruritus severity, according to VAS and the four-item itch questionnaire score, was statistically significantly higher in patients with fibromyalgia than in patients without fibromyalgia (p = 0.027, p = 0.002, respectively). In addition, the number of patients with severe/very severe chronic pruritus was statistically significantly higher in the group accompanied by fibromyalgia (p = 0.023). It may be suggested that fibromyalgia is a frequent disease that can accompany chronic pruritus. Clinicians should keep in mind that there is a possibility of the coexistence of both diseases. This study calls attention to the complex relationship between chronic itch and pain.
Subject(s)
Fibromyalgia , Pruritus , Severity of Illness Index , Humans , Fibromyalgia/epidemiology , Fibromyalgia/diagnosis , Fibromyalgia/complications , Pruritus/diagnosis , Pruritus/etiology , Pruritus/epidemiology , Female , Middle Aged , Male , Adult , Chronic Disease , Surveys and Questionnaires , Aged , Case-Control StudiesABSTRACT
BACKGROUND: Chronic kidney disease-associated pruritus (CKD-ap) is a common complication that negatively affects the quality of life. Difelikefalin has emerged as a novel FDA-approved drug to manage CKD-ap. This systematic review and meta-analysis will assess the efficacy and safety of Difelikefalin versus placebo to manage CKD-ap. METHODS: PubMed, Scopus, WOS, Central, and Embase were systematically searched until November 2023. RevMan was used to perform meta-analysis. Quality assessment was conducted using the Cochrane RoB 2.0 tool. Results were reported as risk ratio (RR) and mean difference (MD) with a 95% confidence interval (CI). PROSPERO ID: (CRD42023485979). RESULTS: Five RCTs with a total of 896 participants were included. Difelikefalin significantly decreased the weekly mean WI-NRS score (MD: -0.99 [-1.22, -0.75], p Ë .00001), 5-D itch scale total score (MD: -1.51 [-2.26, -0.76], p > .0001), and Skindex-10 total score (MD: -7.39 [-12.51, -2.28], p = .005), but showed significantly higher adverse events (RR: 1.26 [1.03, 1.55], p = .03), versus placebo. However, there was no significant difference between both groups in serious adverse events (RR: 1.42 [0.78, 2.57], p = .25) or death (RR: 0.81 [0.19, 3.34], p = .77). CONCLUSION: Difelikefalin appears to be a promising agent for the management of CKD-induced pruritus in patients with end-stage renal disease. However, evidence is still underpowered due to the paucity of the current data; therefore, more robust RCTs are required to confirm the benefit of Difelikefalin.
Subject(s)
Pruritus , Quality of Life , Randomized Controlled Trials as Topic , Renal Dialysis , Renal Insufficiency, Chronic , Humans , Pruritus/drug therapy , Pruritus/etiology , Renal Dialysis/adverse effects , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy , Treatment Outcome , Antipruritics/therapeutic use , Antipruritics/adverse effects , PiperidinesABSTRACT
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
Subject(s)
Dermatitis, Atopic , Interleukin-13 , Interleukins , Prurigo , Pruritus , Humans , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Dermatitis, Atopic/immunology , Prurigo/metabolism , Prurigo/pathology , Prurigo/genetics , Female , Adult , Male , Interleukin-13/metabolism , Interleukin-13/genetics , Interleukins/metabolism , Interleukins/genetics , Pruritus/metabolism , Pruritus/genetics , Middle Aged , Interleukin-4/metabolism , Interleukin-4/genetics , Chronic Disease , Skin/metabolism , Skin/pathology , Young Adult , Interleukin-13 Receptor alpha1 Subunit/metabolism , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-13 Receptor alpha2 Subunit/metabolism , Interleukin-13 Receptor alpha2 Subunit/geneticsABSTRACT
Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
Subject(s)
Hydroxychloroquine , Mice, Knockout , Pruritus , Receptors, Lysophosphatidic Acid , Animals , Receptors, Lysophosphatidic Acid/metabolism , Receptors, Lysophosphatidic Acid/genetics , Pruritus/chemically induced , Pruritus/metabolism , Pruritus/genetics , Pruritus/drug therapy , Mice , Hydroxychloroquine/pharmacology , Ganglia, Spinal/metabolism , Ganglia, Spinal/drug effects , Male , Phosphoric Diester Hydrolases/metabolism , Phosphoric Diester Hydrolases/genetics , Lysophospholipids/metabolism , Mice, Inbred C57BL , Signal Transduction/drug effectsSubject(s)
Antibodies, Monoclonal, Humanized , Blister , Epidermolysis Bullosa , Pruritus , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Pruritus/drug therapy , Epidermolysis Bullosa/drug therapy , Epidermolysis Bullosa/complications , Blister/drug therapy , Female , Male , Adult , Treatment OutcomeABSTRACT
PURPOSE: The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives. MATERIALS AND METHODS: This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed. RESULTS: Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 - 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 - 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16]. CONCLUSIONS: This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.
Subject(s)
Mast Cells , Omalizumab , Pruritus , Humans , Omalizumab/therapeutic use , Omalizumab/administration & dosage , Female , Pruritus/drug therapy , Pruritus/etiology , Male , Middle Aged , Retrospective Studies , Adult , Mast Cells/drug effects , Mast Cells/immunology , Anti-Allergic Agents/therapeutic use , Anti-Allergic Agents/administration & dosage , Treatment Outcome , Severity of Illness Index , Urticaria/drug therapyABSTRACT
Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone-ether-water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.
Subject(s)
Acetone , Extracellular Signal-Regulated MAP Kinases , Pruritus , Receptors, Histamine H4 , Spinal Cord , Animals , Pruritus/chemically induced , Pruritus/metabolism , Receptors, Histamine H4/metabolism , Mice , Spinal Cord/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Male , Acetone/pharmacology , Water , Ether , Disease Models, Animal , Phosphorylation , Indoles/pharmacology , Butadienes/pharmacology , Piperazines/pharmacology , Nitriles/pharmacology , Skin/metabolism , Chronic Disease , Methylhistamines , Proto-Oncogene Proteins c-fos/metabolism , Mice, Inbred C57BLABSTRACT
Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch.