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Although evolutionarily conserved to expel ectoparasites and aid in the clearance of toxins and noxious environmental stimuli from the host, the type 2 immune response can become pathologic in the setting of a variety of allergic disorders. Itch can be a behavioral extension of type 2 immunity by evoking scratching and, in the setting of disease, can become chronic and thus highly pathologic as well. Classically, our understanding of itch mechanisms has centered around the canonical IgE-mast cell-histamine axis. However, therapies aimed at blocking the histaminergic itch pathway have been largely ineffective, suggesting the existence of nonhistaminergic itch pathways. Indeed, recent advances in itch biology have provided critical new insight into a variety of novel therapeutic avenues for chronic itch in the setting of a number of allergic disorders. Here we highlight how these new developments will likely inform the problem of pruritus in a variety of well-established and emerging conditions in the field of allergy.
Learn More >Dermatological manifestations are common in systemic diseases, such as chronic kidney disease. The present study investigated the clinical features and possible influencing factors of pruritus in patients with chronic renal failure (CRF). A total of 382 inpatients were enrolled from the Department of Nephrology at The Second Affiliated Hospital of Chongqing Medical University. A total of 138 subjects were hemodialysis patients, 41 were peritoneal dialysis patients, and 203 were chronic renal failure patients. The patients' clinical performance was observed, and the data was recorded for analysis. The prevalence of pruritus in hemodialysis patients was greater than that in peritoneal dialysis patients. A total of 187 patients were accompanied by xerodermia and 109 patients had pruritus at the same time. With effective and regular dialysis, pruritus could be alleviated in 40% of patients. The intensity of pruritus in the enrolled patients ranged from mild itching to irritability during day and night periods. Moreover, pruritus was intermittent or persistent, and/or limited to generalized. Following treatment, 35% of patients had poor results. A significant difference was noted in the levels of serum urea nitrogen, creatinine, serum phosphorus, calcium × phosphorus, and parathyroid hormone (PTH) between patients with pruritus and non-pruritus. Xerodermia is a common skin manifestation in patients with chronic renal failure and is associated with the occurrence of pruritus. Local cold and heat stimulation can relieve pruritus to some extent, and adequate hemodialysis can also relieve itching.
Learn More >: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. : This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. : There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.
Learn More >The spinal administration of opioids can cause intense pruritisInteractions between specific μ-opioid receptor isoforms and the gastrin releasing peptide receptor in spinal tissues likely mediate morphine-induced pruritus WHAT THIS ARTICLE TELLS US THAT IS NEW: Human spinal cord tissue expresses the 1Y isoform of the μ-opioid receptor, and that isoform functionally interacts with the gastrin releasing peptide receptor to cause cellular calcium influxBlocking interactions between the 1Y isoform and the gastrin releasing peptide receptor does not reduce opioid analgesiaEliminating interactions between the 1Y isoform and the gastrin releasing peptide receptor or reducing 1Y isoform activation may reduce opioid-induced pruritis BACKGROUND:: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between μ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific μ-opioid receptor isoforms which interact with gastrin releasing peptide receptor.
Learn More >Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders.
Learn More >Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8-22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.
Learn More >Acute itch can be generated by either chemical or mechanical stimuli, which activate separate pathways in the periphery and spinal cord. While substantial progress has been made in mapping the transmission pathway for chemical itch, the central pathway for mechanical itch remains obscure. Using complementary genetic and pharmacological manipulations, we show that excitatory neurons marked by the expression of the neuropeptide Y1 receptor (Y1 neurons) form an essential pathway in the dorsal spinal cord for the transmission of mechanical but not chemical itch. Ablating or silencing the Y1 neurons abrogates mechanical itch, while chemogenetic activation induces scratching. Moreover, using Y1 conditional knockout mice, we demonstrate that endogenous neuropeptide Y (NPY) acts via dorsal-horn Y1-expressing neurons to suppress light punctate touch and mechanical itch stimuli. NPY-Y1 signaling thus regulates the transmission of innocuous tactile information by establishing biologically relevant thresholds for touch discrimination and mechanical itch reflexes.
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