The goal of this study was to test whether central mechanisms of scratching-induced itch attenuation can be activated by scratching the limb contralateral to the itching limb when the participant is made to visually perceive the non-itching limb as the itching limb by means of mirror images.
- Proceedings of the National Academy of Sciences of the United States of America
- Published almost 5 years ago
Watching someone scratch himself can induce feelings of itchiness in the perceiver. This provides a unique opportunity to characterize the neural basis of subjective experiences of itch, independent of changes in peripheral inputs. In this study, we first established that the social contagion of itch is essentially a normative response (experienced by most people), and that the degree of contagion is related to trait differences in neuroticism (i.e., the tendency to experience negative emotions), but not to empathy. Watching video clips of someone scratching (relative to control videos of tapping) activated, as indicated by functional neuroimaging, many of the neural regions linked to the physical perception of itch, including anterior insular, primary somatosensory, and prefrontal (BA44) and premotor cortices. Moreover, activity in the left BA44, BA6, and primary somatosensory cortex was correlated with subjective ratings of itchiness, and the responsivity of the left BA44 reflected individual differences in neuroticism. Our findings highlight the central neural generation of the subjective experience of somatosensory perception in the absence of somatosensory stimulation. We speculate that the habitual activation of this central “itch matrix” may give rise to psychogenic itch disorders.
Abstract Background: Pruritus ani (PA) is defined as intense chronic itching affecting perianal skin. Objective: We aimed to determine the efficacy of topical tacrolimus treatment in atopic dermatitis (AD) patients who have PA. Methods: The study included 32 patients with AD who were suffering PA. Patients were randomized into two groups. In total, 16 patients used 0.03% tacrolimus ointment and 16 patients used Vaseline® as placebo. All groups applied topical treatments to their perianal area twice daily for 4 weeks. The treatments were then reversed for 4 weeks after a 2 weeks wash out period. Results: In total, 32 patients with AD who had refractory anal itching were enrolled in the present study. None of the patients had obtained successful results with previous treatments. There was a statistically significant decrease in the recorded EASI, DLQI and itching scores for the tacrolimus group compared to the placebo groupat weeks 4 and 6 of treatment (p < 0.05). Conclusion: Topical tacrolimus treatment was well tolerated and effective in controlling persistent PA in AD patients.
IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy
- Proceedings of the National Academy of Sciences of the United States of America
- Published 11 months ago
Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO2 Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca(2+) influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD.
Light mechanical stimulation of hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors; however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of neurons that express the gastrin-releasing peptide receptor. Thus, our studies reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch.
“Contagious itch” has been anecdotally reported and recently confirmed in a controlled setting in humans. Here, we investigated in adult rhesus macaques whether ‘contagious itch’ occurs spontaneously in monkeys. In a first experiment, the latency to scratch following cage-mate scratching was observed in pair-housed adult rhesus macaques. Scratching increased within the first 60 s and subsequently declined. In a second experiment, scratching behavior was recorded for individually caged adult rhesus macaques which where shown videos of monkeys scratching, but also neutral stimuli. A greater frequency of scratching was observed when monkeys viewed a video sequence of another monkey scratching as well as during the neutral stimulus immediately following the monkey scratching segment. In conclusion, viewing other monkeys scratching significantly increased scratching behavior in adult rhesus macaques.
Research over the past 15 years has helped to clarify the anatomy and physiology of itch, the clinical features of neuropathic itch syndromes and the scientific underpinning of effective treatments. Two itch-sensitive pathways exist: a histamine-stimulated pathway that uses mechanically insensitive C-fibres, and a cowhage-stimulated pathway primarily involving polymodal C-fibres. Interactions with pain continue to be central to explaining various aspects of itch. Certain spinal interneurons (Bhlhb5) inhibit itch pathways within the dorsal horn; they may represent mediators between noxious and pruritic pathways, and allow scratch to inhibit itch. In the brain, functional imaging studies reveal diffuse activation maps for itch that overlap, but not identically, with pain maps. Neuropathic itch syndromes are chronic itch states due to dysfunction of peripheral or central nervous system structures. The most recognized are postherpetic itch, brachioradial pruritus, trigeminal trophic syndrome, and ischaemic stroke-related itch. These disorders affect a patient’s quality of life to a similar extent as neuropathic pain. Treatment of neuropathic itch focuses on behavioural interventions (e.g., skin protection) followed by stepwise trials of topical agents (e.g., capsaicin), antiepileptic drugs (e.g., gabapentin), injection of other agents (e.g., botulinum A toxin), and neurostimulation techniques (e.g., cutaneous field stimulation). The involved mechanisms of action include desensitization of nerve fibres (in the case of capsaicin) and postsynaptic blockade of calcium channels (for gabapentin). In the future, particular histamine receptors, protease pathway molecules, and vanilloids may serve as targets for novel antipruritic agents.
The terminology used to describe neuropathic pain appears to be conserved across languages, which facilitates the translation of validated neuropathic pain screening tools into other languages. However, this assumption has not been assessed in an African language. Therefore we investigated the terminology used by 54 patients whose native language was isiZulu, a major Bantu language of Africa, when describing their symptomatic HIV-associated sensory neuropathy. Also, because English is a commonly spoken second-language in the region, we assessed these patients' knowledge and understanding of 21 English terms commonly used to describe neuropathic pain. English translations of the most commonly used isiZulu symptom descriptors included: “hot/burning” (50%), “cramping” (35%), “painful/sore/aching” (32%), “itching” (22%), “numb” (22%), “cold/freezing” (17%), and “stabbing/pricking/pins-and-needles” (13%). Thus, the isiZulu terminology to describe neuropathic pain was very similar to that used in non-African languages. However, knowledge and understanding of English neuropathic pain descriptors by these non-native English speakers was highly variable. For example, knowledge of English terms ranged from>98% (“hot”, “cold/freezing”, “cramping”) to <25% ("pricking", "radiating", "throbbing"), and true understanding of English terms ranged from>90% (“hot”, “burning”, “cramping”) to <35% ("tingling", "jumping", "shooting", "radiating"). In conclusion, we show significant similarity in the terms used to describe neuropathic pain in isiZulu compared to non-African languages, thus indicating that translation of existing neuropathic pain screening tools into this, and possibly other Bantu languages, is a viable option. However, the usefulness of English-language screening tools in this non-native English speaking population may be limited.
The thermoreceptive transient receptor potential ankyrin 1 (TRPA1) is important in the transmission of itch, and its agonist trans-cinnamaldehyde has occasionally been reported to be a pruritogen in humans. However, no studies have accurately quantified the capabilities of trans-cinnamaldehyde to induce itch and related dysesthetic sensations. The present study examined alterations in somatosensory and vasomotor parameters in response to topical trans-cinnamaldehyde 5% and vehicle (ethanol) in 24 healthy subjects. During the study the following parameters were recorded: itch area and intensity, hyperknesis, alloknesis, neurogenic flare, skin blood flow and temperature. Trans-cinnamaldehyde evoked moderate itch sensation, flare, hyperknesis and alloknesis (p < 0.001). Blood flow and skin temperature were elevated in the area of trans-cinnamaldehyde application (p < 0.001). Significant positive correlations were found between blood flow and skin temperature, itch area and blood flow, and itch area and skin temperature. Topical trans-cinnamaldehyde proved feasible as a human itch model with applicability in studying itch mechanisms or anti-pruritic drug profiling.
Within the last decade understanding of the mechanistic basis of itch has improved significantly, resulting in the development of several human surrogate models of itch and related dysesthetic states. Well-characterized somatosensory models are useful in basic studies in healthy volunteers, in clinical studies for diagnostic and segmentation purposes, and in pharmacological studies to evaluate the antipruritic efficacy of existing and novel compounds. This review outlines recently introduced histamine-independent human models of itch, their mechanisms, their ability to induce clinically relevant phenomena, such as alloknesis, and the results obtained through their use. The article also introduces recent advances in the understanding of itch and provides an overview of the methods to assess experimentally-induced itch and associated manifestations. Major improvements are warranted in the treatment of chronic pruritus, and reliable human surrogate models are a valuable tool in achieving them, both for basic researchers and for clinicians.