scholarly journals Itch Signaling in the Nervous System

Physiology ◽  
2011 ◽  
Vol 26 (4) ◽  
pp. 286-292 ◽  
Author(s):  
Joseph Jeffry ◽  
Seungil Kim ◽  
Zhou-Feng Chen
Keyword(s):  
Molecular Mechanisms ◽  
Somatosensory System ◽  
Mouse Genetics ◽  
Molecular Signaling ◽  
C Fibers ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Somatic Sensation ◽  
Psychophysical Studies ◽  
Important Progress

Itch is a major somatic sensation, along with pain, temperature, and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated with mosquito bite, or a chronic condition, like atopic dermatitis ( 29 , 59 ). The origins of the stimulus can be localized in the periphery or systemic, and associated with organ failure or cancer. Itch is also a perception originating in the brain. Itch is broadly characterized as either histamine-dependent (histaminergic) or histamine-independent (nonhistaminergic), both of which are relayed by subsets of C fibers and by the second-order neurons expressing gastrin-releasing peptide receptor (GRPR) and spinothalamic track (STT) neurons in the spinal cord of rodents. Historically, itch research has been primarily limited to clinical and psychophysical studies and to histamine-mediated mechanisms. In contrast, little is known about the signaling mechanisms underlying nonhistaminergic itch, despite the fact that the majority of chronic itch are mediated by nonhistaminergic mechanisms. During the past few years, important progress has been made in understanding the molecular signaling of itch, largely due to the introduction of mouse genetics. In this review, we examine some of the molecular mechanisms underlying itch sensation with an emphasis on recent studies in rodents.

scholarly journals Molecular signature of pruriceptive MrgprA3+ neurons

2019 ◽  
Author(s):  
Yanyan Xing ◽  
Junyu Chen ◽  
Henry Hilley ◽  
Haley Steele ◽  
Jingjing Yang ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Neuronal Populations ◽  
Pathological Conditions ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Profile Changes ◽  
Allergic Contact

ABSTRACTItch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals The C. elegans Hypertonic Stress Response: Big Insights from Shrinking Worms

2020 ◽  
Vol 55 (S1) ◽  
pp. 89-105
Keyword(s):  
Stress Response ◽  
Cell Volume ◽  
Molecular Mechanisms ◽  
Model Organism ◽  
Future Research ◽  
Transcriptional Level ◽  
Molecular Signaling ◽  
Hypertonic Stress ◽  
Macromolecular Assemblies ◽  
C Elegans

Cell volume is one of the most aggressively defended physiological set points in biology. Changes in intracellular ion and water concentrations, which are induced by changes in metabolism or environmental exposures, disrupt protein folding, enzymatic activity, and macromolecular assemblies. To counter these challenges, cells and organisms have evolved multifaceted, evolutionarily conserved molecular mechanisms to restore cell volume and repair stress induced damage. However, many unanswered questions remain regarding the nature of cell volume 'sensing' as well as the molecular signaling pathways involved in activating physiological response mechanisms. Unbiased genetic screening in the model organism C. elegans is providing new and unexpected insights into these questions, particularly questions relating to the hypertonic stress response (HTSR) pathway. One surprising characteristic of the HTSR pathway in C. elegans is that it is under strong negative regulation by proteins involved in protein homeostasis and the extracellular matrix (ECM). The role of the ECM in particular highlights the importance of studying the HTSR in the context of a live organism where native ECM-tissue associations are preserved. A second novel and recently discovered characteristic is that the HTSR is regulated at the post-transcriptional level. The goal of this review is to describe these discoveries, to provide context for their implications, and to raise outstanding questions to guide future research.

Response Properties of Mechanoreceptors and Nociceptors in Mouse Glabrous Skin: An In Vivo Study

2001 ◽  
Vol 85 (4) ◽  
pp. 1561-1574 ◽  
Author(s):  
David M. Cain ◽  
Sergey G. Khasabov ◽  
Donald A. Simone
Keyword(s):  
Transgenic Mice ◽  
Somatosensory System ◽  
Glabrous Skin ◽  
In Vivo Study ◽  
Response Properties ◽  
C Fibers ◽  
Afferent Fibers ◽  
Response Thresholds ◽  
Thermal Stimuli

The increasing use of transgenic mice for the study of pain mechanisms necessitates comprehensive understanding of the murine somatosensory system. Using an in vivo mouse preparation, we studied response properties of tibial nerve afferent fibers innervating glabrous skin. Recordings were obtained from 225 fibers identified by mechanical stimulation of the skin. Of these, 106 were classed as Aβ mechanoreceptors, 51 as Aδ fibers, and 68 as C fibers. Aβ mechanoreceptors had a mean conduction velocity of 22.2 ± 0.7 (SE) m/s (13.8–40.0 m/s) and a median mechanical threshold of 2.1 mN (0.4–56.6 mN) and were subclassed as rapidly adapting (RA, n = 75) or slowly adapting (SA, n = 31) based on responses to constant force mechanical stimuli. Conduction velocities ranged from 1.4 to 13.6 m/s (mean 7.1 ± 0.6 m/s) for Aδ fibers and 0.21 to 1.3 m/s (0.7 ± 0.1 m/s) for C fibers. Median mechanical thresholds were 10.4 and 24.4 mN for Aδ and C fibers, respectively. Responses of Aδ and C fibers evoked by heat (35–51°C) and by cold (28 to −12°C) stimuli were determined. Mean response thresholds of Aδ fibers were 42.0 ± 3.1°C for heat and 7.6 ± 3.8°C for cold, whereas mean response thresholds of C fibers were 40.3 ± 0.4°C for heat and 10.1 ± 1.9°C for cold. Responses evoked by heat and cold stimuli increased monotonically with stimulus intensity. Although only 12% of tested Aδ fibers were heat sensitive, 50% responded to cold. Only one Aδ nociceptor responded to both heat and cold stimuli. In addition, 40% of Aδ fibers were only mechanosensitive since they responded neither to heat nor to cold stimuli. Thermal stimuli evoked responses from the majority of C fibers: 82% were heat sensitive, while 77% of C fibers were excited by cold, and 68% were excited by both heat and cold stimuli. Only 11% of C fibers were insensitive to heat and/or cold. This in vivo study provides an analysis of mouse primary afferent fibers innervating glabrous skin including new information on encoding of noxious thermal stimuli within the peripheral somatosensory system of the mouse. These results will be useful for future comparative studies with transgenic mice.

scholarly journals No significant relation of proinflammatory slanDCs with uremic pruritus

2020 ◽  
Vol 18 ◽  
pp. 205873922092685
Author(s):  
Christof Ulrich ◽  
Anja Leonhardt ◽  
Bogusz Trojanowicz ◽  
Eric Seibert ◽  
Roman Fiedler ◽  
...  
Keyword(s):  
Life Quality ◽  
Binary Logistic Regression ◽  
Monocyte Subset ◽  
Inclusion Criteria ◽  
Binary Logistic Regression Model ◽  
Uremic Pruritus ◽  
Chronic Itch ◽  
Itch Sensation ◽  
Study Inclusion

The pathogenesis of the pruritus associated with chronic kidney disease-(CKD-aP) is not completely understood. Endocrine, metabolic, neuropathic, and inflammatory disorders were suspected to be the origin of CKD-aP. Based on the hypothesis which suggests that deregulated systemic inflammation may play a crucial role in CKD-a, we investigated the potential relation of an inflammatory monocyte subset (slanDCs) with CKD-aP. Itch questionnaire, visual analogue scale (VAS)-scoring, and Dermatology Life Quality Index (DQLI) were applied for the characterization of itch sensation. VAS-scoring was re-evaluated after 6 months. Monocytes were flow-cytometrically categorized into classical, intermediate, and non-classical subsets. slanDCs are part of the non-classical monocyte subpopulation. Sixty-six hemodialysis patients (CKD5-D) were screened of whom 43 met the study inclusion criteria. In all, 46.5% of patients were scored pruritus-positive (CKD-aP+). CKD-aP severity level of patients was moderate at the start of the study (VAS 5.3 ± 2.5) and remained unchanged after 6 months (VAS: 5.2 ± 1.9, P < 0.757). Thirty percent of patients were affected with mild, 30.0% with moderate, and 35.0% with severe itchiness. In contrast to all other factors tested solely slanDC showed a weak correlation to VAS-score (r = 0.41, P = 0.07). slanDC frequencies between CKD5-D patients with and without itch sensation, however, were not significantly different. Endocrine problems appeared to influence CKD-aP. CKD-aP + patients had significantly higher L-thyroxin supplementation than CKD-aP- (50.0% vs 8.7%, P < 0.005). A binary logistic regression model confirmed the significance of L-thyroxin medication on chronic itch problems of our CKD5-D patients ( P < 0.007). There is no clear evidence that slanDCs are related to uremic pruritus. Therefore, other factors underlie the pathophysiology of CKD-aP.

The Parallel Signaling Pathways Of Phosphatidylserine (PS) Exposure Downstream Of Platelet FcγRIIa

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3514-3514 ◽  
Author(s):  
Pierrette Andre ◽  
Steven E. McKenzie ◽  
Wolfgang Bergmeier
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Annexin V ◽  
Therapeutic Benefit ◽  
Human Platelets ◽  
Molecular Signaling ◽  
P2y12 Inhibitor ◽  
Immune Mediated ◽  
Static Conditions

Abstract Platelet FcγRIIa is an important component of heparin-induced thrombocytopenia and other immune-mediated thrombocytopenia and thrombosis syndromes. Platelet FcγRIIa, an ITAM receptor, signals not only to cause aggregation and secretion, but also to PS exposure in the platelet procoagulant response when platelets are co-stimulated via the GCPR PARs. The molecular mechanisms downstream of FcγRIIa that lead to PS exposure are incompletely understood. Recently, we (WB; Ahmad et al., JTH 2011; 9:2077) demonstrated that downstream of PAR and GPVI/FcRγ, another ITAM receptor, there are CalDAG-GEF I (CDGI)-dependent and CDGI-independent, ADP/P2Y12-dependent parallel signaling pathways to PS exposure. In this study, we investigated the molecular signaling requirements for PS exposure downstream of FcγRIIa + PAR dual stimulation. We studied the exposure of PS in FcγRIIa transgenic (tg) mouse platelets following dual stimulation through FcγRIIa via anti-mouse CD9 and through PAR4 via PAR4 activating peptide (PAR4AP; AYPGKF). Washed platelets from FcγRIIa-tg mice and FcγRIIa-tg/CDG1-/- mice were stimulated with varying concentrations of anti-mouse CD9 and PAR4-AP (200uM) under static conditions and immediately measured for PS exposure by labeled Annexin-V in flow cytometry. We observed that at 0.5ug/ml of anti-mouse CD9 that the PS exposure of the FcγRIIa-tg/CDG1-/- platelets is approximately 70% of the FcγRIIa-tg platelets. However, when the platelets are pre-incubated with P2Y12 inhibitor MesAMP at 100uM, the PS exposure of the FcγRIIa-tg platelets is decreased by approximately 50% (n=3). For the FcγRIIa-tg/CDG1-/- platelets in the presence of MesAMP, PS exposure is completely abolished (n=3). This indicates that CDG1 contributes part of the signal that leads to PS exposure, while ADP/P2Y12 contributes the other CDGI-independent part of PS exposure downstream of FcγRIIa and GPCR dual stimulation. At a lower concentration of anti-mouse CD9 (0.25ug/ml; near threshold), the level of PS exposure of the FcγRIIa-tg/CDG1-/- platelets is approximately 80% of the FcgRIIa-tg platelets. In addition, at 0.25 ug/ml of anti-CD9, FcγRIIa-tg/CDG1-/- platelets pre-incubated with the P2Y12 inhibitor revealed no stimulated PS exposure. This observation indicates that ADP/P2Y12 plays a more significant role in PS exposure as the concentration of FcγRIIa stimulant nears threshold. Eradication of procoagulant PS exposure may require targeting of both the CDGI-dependent and CDGI-independent pathways for optimum therapeutic benefit in HIT and other immune-mediated thrombocytopenia and thrombosis disorders. CDGI inhibitors useful in human platelets will allow translation of these findings. Disclosures: No relevant conflicts of interest to declare.

New mechanisms and targets in the treatment of bone fragility

2006 ◽  
Vol 112 (2) ◽  
pp. 77-91 ◽  
Author(s):  
T. John Martin ◽  
Ego Seeman
Keyword(s):  
Bone Formation ◽  
Molecular Mechanisms ◽  
Regulatory System ◽  
Bone Fragility ◽  
Mouse Genetics ◽  
Mineral Density ◽  
Structural Determinants ◽  
Tissue Mass ◽  
Bone Modelling ◽  
Anabolic Therapy

Bone modelling and remodelling are cell-mediated processes responsible for the construction and reconstruction of the skeleton throughout life. These processes are chiefly mediated by locally generated cytokines and growth factors that regulate the differentiation, activation, work and life span of osteoblasts and osteoclasts, the cells that co-ordinate the volumes of bone resorbed and formed. In this way, the material composition and structural design of bone is regulated in accordance with its loading requirements. Abnormalities in this regulatory system compromise the material and structural determinants of bone strength producing bone fragility. Understanding the intercellular control processes that regulate bone modelling and remodelling is essential in planning therapeutic approaches to prevention and treatment of bone fragility. A great deal has been learnt in the last decade. Clinical trials carried out exclusively with drugs that inhibit bone resorption have identified the importance of reducing the rate of bone remodelling and so the progression of bone fragility to achieved fracture reductions of approx. 50%. These trials have also identified limitations that should be placed upon interpretation of bone mineral density changes in relation to treatment. New resorption inhibitors are being developed, based on mechanisms of action that are different from existing drugs. Some of these might offer resorption inhibition without reducing bone formation. More recent research has provided the first effective anabolic therapy for bone reconstruction. Daily injections of PTH (parathyroid hormone)-(1–34) have been shown in preclinical studies and in a large clinical trial to increase bone tissue mass and reduce the risk of fractures. The action of PTH differs from that of the resorption inhibitors, but whether it is more effective in fracture reduction is not known. Understanding the cellular and molecular mechanisms of PTH action, particularly its interactions with other pathways in determining bone formation, is likely to lead to new therapeutic developments. The recent discovery through mouse genetics that PTHrP (PTH-related protein) is a crucial bone-derived paracrine regulator of remodelling offers new and interesting therapeutic targets.

Distribution of genes for parathyroid hormone (PTH)—related peptide, Indian hedgehog, PTH receptor and patched in the process of experimental spondylosis in mice

2002 ◽  
Vol 97 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Takanobu Nakase ◽  
Kenta Ariga ◽  
Wenxiang Meng ◽  
Motoki Iwasaki ◽  
Tetsuya Tomita ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Indian Hedgehog ◽  
Molecular Signaling ◽  
Content Type ◽  
Chondrocyte Maturation ◽  
Related Peptide ◽  
Fine Print

Object. Little is known about the molecular mechanisms underlying the process of spondylosis. The authors determined the extent of genetic localization of major regulators of chondrogenesis such as Indian hedgehog (Ihh) and parathyroid hormone (PTH)—related peptide (PTHrP) and their receptors during the development of spondylosis in their previously established experimental mouse model. Methods. Experimental spondylosis was induced in 5-week-old ICR mice. The cervical spines were chronologically harvested, and histological sections were prepared. Messenger (m) RNA for PTHrP, Ihh, PTH receptor (PTHR; a receptor for PTHrP), patched (Ptc; a receptor for Ihh), bone morphogenetic protein (BMP)—6, and collagen type X (COL10; a marker for mature chondrocyte) was localized in the tissue sections by performing in situ hybridization. In the early stage, mRNA for COL10, Ihh, and BMP-6 was absent; however, mRNA for PTHrP, PTHR, and Ptc was detected in the anterior margin of the cervical discs. In the late stage, evidence of COL10 mRNA began to be detected, and transcripts for Ihh, PTHrP, and BMP-6 were localized in hypertrophic chondrocytes adjacent to the bone-forming area in osteophyte. Messenger RNA for Ptc and PTHR continued to localize at this stage. In control mice, expression of these genes was absent. Conclusions. The localization of PTHrP, Ihh, BMP-6, and the receptors PTHR and Ptc demonstrated in the present experimental model indicates the possible involvement of molecular signaling by PTHrP (through the PTHR), Ihh (through the Ptc), and BMP-6 in the regulation of chondrocyte maturation leading to endochondral ossification in spondylosis.

scholarly journals The Role of Transient Receptor Potential A1 and G Protein-Coupled Receptor 39 in Zinc-Mediated Acute and Chronic Itch in Mice

2022 ◽  
Vol 14 ◽  
Author(s):  
Yue Hu ◽  
Qing-Yue Fu ◽  
Dan-Ni Fu ◽  
Xue-Long Wang ◽  
Zhi-Hong Wang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Systemic Administration ◽  
Common Symptom ◽  
Dry Skin ◽  
C Fibers ◽  
Transient Receptor Potential A1 ◽  
Chronic Itch ◽  
Transient Receptor

Itching is a common symptom of many skin or systemic diseases and has a negative impact on the quality of life. Zinc, one of the most important trace elements in an organism, plays an important role in the regulation of pain. Whether and how zinc regulates itching is largely unclear. Herein, we explored the role of Zn2+ in the regulation of acute and chronic itch in mice. It is found that intradermal injection (i.d.) of Zn2+ dose-dependently induced acute itch and transient receptor potential A1 (TRPA1) participated in Zn2+-induced acute itch in mice. Moreover, the pharmacological analysis showed the involvement of histamine, mast cells, opioid receptors, and capsaicin-sensitive C-fibers in Zn2+-induced acute itch in mice. Systemic administration of Zn2+ chelators, such as N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), pyrithione, and clioquinol were able to attenuate both acute itch and dry skin-induced chronic itch in mice. Quantitative polymerase chain reaction (Q-PCR) analysis showed that the messenger RNA (mRNA) expression levels of zinc transporters (ZIPs and ZnTs) significantly changed in the dorsal root ganglia (DRG) under dry skin-induced chronic itch condition in mice. Activation of extracellular signal-regulated kinase (ERK) pathway was induced in the DRG and skin by the administration of zinc or under dry skin condition, which was inhibited by systemic administration of Zn2+ chelators. Finally, we found that the expression of GPR39 (a zinc-sensing GPCR) was significantly upregulated in the dry skin mice model and involved in the pathogenesis of chronic itch. Together, these results indicated that the TRPA1/GPR39/ERK axis mediated the zinc-induced itch and, thus, targeting zinc signaling may be a promising strategy for anti-itch therapy.

scholarly journals Electrically Evoked Itch in Human Subjects

2021 ◽  
Vol 7 ◽  
Author(s):  
Hans Jürgen Solinski ◽  
Roman Rukwied
Keyword(s):  
Electrical Stimulation ◽  
Action Potentials ◽  
Human Subjects ◽  
Electrical Activation ◽  
Peripheral Neurons ◽  
The Past ◽  
C Fibers ◽  
Chronic Itch ◽  
Transduction Mechanisms ◽  
The Central Nervous System

Administration of chemicals (pruritogens) into the skin evokes itch based on signal transduction mechanisms that generate action potentials mainly in mechanically sensitive and insensitive primary afferent C-fibers (pruriceptors). These signals from peripheral neurons are processed in spinal and supra-spinal centers of the central nervous system and finally generate the sensation of itch. Compared to chemical stimulation, electrical activation of pruriceptors would allow for better temporal control and thereby a more direct functional assessment of their activation. Here, we review the electrical stimulation paradigms which were used to evoke itch in humans in the past. We further evaluate recent attempts to explore electrically induced itch in atopic dermatitis patients. Possible mechanisms underlying successful pruritus generation in chronic itch patients by transdermal slowly depolarizing electrical stimulation are discussed.

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