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Skin is among the first and most heavily damaged organs upon sulphur mustard (SM) exposure. Pruritus is the most common chronic skin complication of SM, which adversely affects the quality of life (QoL). However, current therapies for the management of SM-induced pruritus are very limited and associated with side effects. The present trial investigated the efficacy of curcumin in the alleviation of SM-induced chronic pruritic symptoms. A total of ninety-six male Iranian veterans (age 37–59 years) were randomised to receive either curcumin (1 g/d, n 46) or placebo (n 50) for 4 weeks. Serum concentrations of substance P and activities of antioxidant enzymes were measured at baseline and at the end of the trial. Assessment of pruritus severity was performed using the pruritus score, visual analogue scale (VAS) and scoring atopic dermatitis (SCORAD) index. QoL was evaluated using the Dermatology Life Quality Index (DLQI) questionnaire. Serum concentrations of substance P (P < 0·001) as well as activities of superoxide dismutase (P = 0·02), glutathione peroxidase (P = 0·006) and catalase (P < 0·001) were significantly reduced in the curcumin group, while no significant change was observed in the placebo group. Curcumin supplementation was also associated with significant reductions in measures of pruritus severity including the pruritus score (P < 0·001), VAS score (P < 0·001), overall (P < 0·001) and objective SCORAD (P = 0·009), and DLQI's first question (P < 0·001). None of these measures was significantly changed in the placebo group. As for the QoL, although DLQI scores decreased in both groups (P < 0·001 and P = 0·003 in the curcumin and placebo groups, respectively), the magnitude of reduction was significantly greater in the curcumin group (P < 0·001). In conclusion, curcumin may be regarded as a natural, safe, widely available and inexpensive treatment for the management of SM-induced chronic pruritus.

Research into placebo effects has convincingly shown that inducing positive outcome expectations can reduce pain and other physical sensations. However, the comparative effects of different expectation inductions, such as verbal suggestion or mental imagery, and their generic effects on physical sensitivity, to different sensations such as pain, itch, and fatigue, are still largely unknown. In the current study, we assessed the individual and combined effects of verbal suggestion and imagery on pain, itch, and fatigue as indicators of physical sensitivity in a randomized study design. Healthy participants (n = 116) were given an inert (placebo) capsule that was said to be effective for reducing physical sensitivity in either the majority (positive verbal suggestion) or the minority (control verbal suggestion) of users. Subsequently, they imagined either their best possible health (positive imagery) or a typical day (control imagery). Sensitivity to pain, itch, and fatigue was tested using a cold pressor test, histamine iontophoresis, and a bicycle test, respectively. Heart rate and skin conductance were recorded continuously. Results showed that positive verbal suggestion and imagery successfully induced positive expectations, but they did not affect physical sensitivity, as indicated by sensitivity to pain, itch, or fatigue, or concurrent physiological responses. These results could indicate that the specificity and concreteness of expectation inductions might be important for their applicability in the treatment of physical symptoms. Nederlands Trial Register NTR3641.

Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing.

Based on single cell RNA-sequencing of 622 adult mouse sensory neurons, Usoskin et al . performed unbiased classification to identify the cellular and molecular complexity underlying somatic sensation. Eleven different subtypes were identified, including some previously unknown populations such as a new class of neuron which may be sensitive to inflammatory itch. The primary sensory system requires the integrated function of multiple cell types, although its full complexity remains unclear. We used comprehensive transcriptome analysis of 622 single mouse neurons to classify them in an unbiased manner, independent of any a priori knowledge of sensory subtypes. Our results reveal eleven types: three distinct low-threshold mechanoreceptive neurons, two proprioceptive, and six principal types of thermosensitive, itch sensitive, type C low-threshold mechanosensitive and nociceptive neurons with markedly different molecular and operational properties. Confirming previously anticipated major neuronal types, our results also classify and provide markers for new, functionally distinct subtypes. For example, our results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type. We demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types. The resulting catalog illustrates the diversity of sensory types and the cellular complexity underlying somatic sensation.

Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch.

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.

Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.

Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb -/- mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb -/- mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.

Neuropathic itch is a type of chronic pruritus resulting from neural dysfunction along the afferent pathway. It is often accompanied by abnormal sensations such as paresthesia, hyperesthesia, or hypoesthesia. This condition, which may involve motor or autonomic neural damage, significantly impacts patients' quality of life, causing severe itch and associated comorbidities such as depression, disrupted sleep, and social strain. Neuropathic itch accounts for 8% of chronic pruritus cases, though this may be underestimated. This comprehensive review focuses on nerve impingement as the primary pathophysiological mechanism for various forms of neuropathic itch including brachioradial pruritus (BRP), notalgia paresthetica (NP), and anogenital itch. BRP, often seen in middle-aged white women, manifests as pruritus in the dorsolateral forearms typically exacerbated by ultraviolet (UV) exposure and related to cervical spine pathology. NP, prevalent in middle-aged women, presents as pruritus in the upper back due to thoracic spine nerve compression. Anogenital pruritus, affecting 1-5% of adults, is often linked to lumbosacral spine issues after ruling out dermatologic conditions such as lichen sclerosus or lichen simplex chronicus. The pathophysiology of neuropathic itch involves both peripheral and central mechanisms, with nerve damage being a key factor. Diagnosis requires a thorough history, physical examination, and potentially imaging studies. Topical agents such as menthol, capsaicin, and lidocaine are used for mild cases, while systemic medications such as gabapentin, pregabalin, and antidepressants are prescribed for moderate to severe cases; however, no US Food and Drug Administration (FDA)-approved therapies currently exist specifically for neuropathic itch. Understanding the underlying neural dysfunction and appropriate therapeutic strategies is crucial for managing neuropathic itch effectively.

Background: Various mediators have been suggested for the pathogenesis of pruritus in psoriasis. Methods: To investigate cutaneous responses of substance P in pruritic lesional and nonlesional areas of psoriasis patients and in healthy controls, substance P, saline and histamine were injected intradermally. After each injection, pruritus, flare and wheal were recorded. Results: There was no statistical difference in the latency period, duration, area under the curve and maximum intensity of pruritus evoked by substance P (10 –5 and 10 –6 mol/l) between psoriasis and healthy control skin. Substance P (10 –5 mol/l) induced a tendency to a greater intensity of pruritus in lesional compared to nonlesional psoriatic skin (p = 0.08). Histamine produced a shorter itch latency period (p < 0.05) and a lower maximum intensity of pruritus (p = 0.05) in lesional psoriasis skin than in healthy control skin. No significant difference in flare area was observed between the psoriasis patients and healthy controls. The histamine-induced wheal was smaller in psoriasis patients than in healthy individuals (p < 0.05). Conclusion: Intradermally injected substance P induced pruritus, flare and wheal in psoriasis patients. However, these responses did not differ significantly from those of the healthy controls.