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1.
Int J Mol Med ; 44(3): 835-846, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257468

RESUMO

In this study, we focused on several itch­related molecules and receptors in the spinal cord with the goal of clarifying the specific mediators that regulate itch sensation. We investigated the involvement of serotonin receptors, opioid receptors, glia cell markers and chemokines (ligands and receptors) in models of acetone/ether/water (AEW)­ and diphenylcyclopropenone (DCP)­induced chronic itch. Using reverse transcription­quantitative polymerase chain reaction, we examined the expression profiles of these mediators in the lower cervical spinal cord (C5­8) of two models of chronic itch. We found that the gene expression levels of opioid receptor mu 1 (Oprm1), 5­hydroxytryptamine receptor 1A (Htr1a) and 5­hydroxytryptamine receptor 6 (Htr6) were upregulated. Among the chemokines, the expression levels of C­C motif chemokine ligand (Ccl)21, Cxcl3 and Cxcl16 and their receptors, Ccr7, Cxcr2 and Cxcr6, were simultaneously upregulated in the spinal cords of the mice in both models of chronic itch. By contrast, the expression levels of Ccl2, Ccl3, Ccl4 and Ccl22 were downregulated. These findings indicate that multiple mediators, such as chemokines in the spinal cord, are altered and may be central candidates in further research into the mechanisms involved in the development of chronic itch.


Assuntos
Biomarcadores , Medula Cervical/metabolismo , Regulação da Expressão Gênica , Prurido/genética , Animais , Biópsia , Quimiocinas/metabolismo , Doença Crônica , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Microglia/metabolismo , Neurônios/metabolismo , Prurido/diagnóstico , Prurido/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Pele/metabolismo , Pele/patologia
2.
Neuron ; 103(1): 102-117.e5, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31103358

RESUMO

Spinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.


Assuntos
Peptídeo Liberador de Gastrina/genética , Prurido/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Neurônios , Optogenética , Bloqueadores dos Canais de Potássio/farmacologia , Prurido/genética , Prurido/psicologia , Receptores da Bombesina/antagonistas & inibidores , Receptores da Bombesina/genética , Receptores de Glutamato/fisiologia , Receptores Pré-Sinápticos/metabolismo , Medula Espinal/citologia
3.
Toxicol In Vitro ; 57: 164-173, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30851411

RESUMO

The incidence of sensitive skin with stinging and itch following chemical exposure in products such as cosmetics is increasing, but molecular mechanisms underlying this pathophysiology remain understudied. Here we performed transcriptional analysis of reconstructed human epidermis (RHE) 1, 6, and 24 h following topical lactic acid (LA) application, a known inducer of the sensitive skin reaction. Since little is known about the specific role of keratinocyte transcriptional changes in mediating stinging and itch, we performed pathway analysis using several publically available databases and then focused on significantly changed transcripts involved in stress responses and itch signaling using the Comparative Toxicogenomics Database. LA treatment induced damage-associated genes HSPA1A, DDIT3, IL1A, and HMGB2. Neurotrophic factors including BDNF, ARTN, PGE2, and chemokines were also upregulated. Stimulation of the RHE with 5% LA did not reduce cell viability, but reduced the trans-epidermal electric resistance, suggesting barrier dysfunction. Accordingly, skin barrier formation genes such as filaggrins (FLG, FLG2) and corneodesmosin (CDSN) were downregulated. To our knowledge, this is the first study focusing on transcriptional changes underlying the stinging response of keratinocytes upon LA stimulation. While follow-up research is needed, this study provides new insight into the mechanisms underlying the sensitive skin reaction.


Assuntos
Epiderme/efeitos dos fármacos , Irritantes/toxicidade , Ácido Láctico/toxicidade , Prurido/genética , Transcriptoma/efeitos dos fármacos , Epiderme/metabolismo , Humanos
4.
J Allergy Clin Immunol ; 143(1): 13-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30612664

RESUMO

Atopic dermatitis (AD) is characterized by severe pruritus and recurrent eczema with a chronic disease course. Impaired skin barrier function, hyperactivated TH2 cell-type inflammation, and pruritus-induced scratching contribute to the disease pathogenesis of AD. Skin microbial alterations complicate the pathogenesis of AD further. Mouse models are a powerful tool to analyze such intricate pathophysiology of AD, with a caution that anatomy and immunology of the skin differ between human subjects and mice. Here we review recent understanding of AD etiology obtained using mouse models, which address the epidermal barrier, skin microbiome, TH2 immune response, and pruritus.


Assuntos
Dermatite Atópica , Pele , Células Th2 , Animais , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Modelos Animais de Doenças , Humanos , Camundongos , Microbiota/imunologia , Prurido/genética , Prurido/imunologia , Prurido/patologia , Prurido/fisiopatologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Pele/fisiopatologia , Células Th2/imunologia , Células Th2/patologia
5.
Proc Natl Acad Sci U S A ; 115(51): E12091-E12100, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30463955

RESUMO

Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of Tmem79, an orphan transmembrane protein linked to AD in both mice and humans. We show that Tmem79 is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic Tmem79 is sufficient to elicit robust scratching. Tmem79 -/- mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79 -/- mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1- afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE2 and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat Tmem79-associated AD itch. Our findings suggest that individuals with mutations in Tmem79 develop AD due to the loss of protection from oxidative stress.


Assuntos
Dermatite Atópica/genética , Proteínas de Membrana/fisiologia , Prurido/genética , Animais , Deleção de Genes , Células HEK293 , Humanos , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Estresse Oxidativo/genética , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais
6.
J Clin Invest ; 128(12): 5434-5447, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30395542

RESUMO

Itch (pruritis) and pain represent two distinct sensory modalities; yet both have evolved to alert us to potentially harmful external stimuli. Compared with pain, our understanding of itch is still nascent. Here, we report a new clinical case of debilitating itch and altered pain perception resulting from the heterozygous de novo p.L811P gain-of-function mutation in NaV1.9, a voltage-gated sodium (NaV) channel subtype that relays sensory information from the periphery to the spine. To investigate the role of NaV1.9 in itch, we developed a mouse line in which the channel is N-terminally tagged with a fluorescent protein, thereby enabling the reliable identification and biophysical characterization of NaV1.9-expressing neurons. We also assessed NaV1.9 involvement in itch by using a newly created NaV1.9-/- and NaV1.9L799P/WT mouse model. We found that NaV1.9 is expressed in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia (DRGs). In WT DRGs, but not those of NaV1.9-/- mice, pruritogens altered action potential parameters and NaV channel gating properties. Additionally, NaV1.9-/- mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas NaV1.9L799P/WT mice displayed increased spontaneous scratching. Altogether, our data suggest an important contribution of NaV1.9 to itch signaling.


Assuntos
Gânglios Espinais , Mutação , Canal de Sódio Disparado por Voltagem NAV1.9 , Neurônios , Prurido , Transdução de Sinais , Animais , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Canal de Sódio Disparado por Voltagem NAV1.9/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Prurido/genética , Prurido/metabolismo , Prurido/patologia
7.
J Neurosci ; 38(46): 9856-9869, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30266741

RESUMO

Itchiness triggers a strong urge to engage in scratching behavior, which could lead to severe skin or tissue damage in patients with chronic itch. This process is dynamically modulated. However, the neural mechanisms underlying itch modulation remain largely unknown. Here, we report that dopaminergic (DA) neurons in the ventral tegmental area (VTA) play a critical role in modulating itch-induced scratching behavior. We found that the activity of VTA DA neurons was increased during pruritogen-induced scratching behavior in freely moving male mice. Consistently, individual VTA DA neurons mainly exhibited elevated neural activity during itch-induced scratching behavior as demonstrated by in vivo extracellular recording. In behavioral experiments, the transient suppression of VTA DA neurons with the optogenetic approach shortened the pruritogen-induced scratching train. Furthermore, the DA projection from the VTA to the lateral shell of the nucleus accumbens exhibited strong activation as measured with fiber photometry during itch-elicited scratching behavior. These results revealed the dynamic activity of VTA DA neurons during itch processing and demonstrated the modulatory role of the DA system in itch-induced scratching behavior.SIGNIFICANCE STATEMENT Itchiness is an unpleasant sensation that evokes a scratching response for relief. However, the neural mechanism underlying the modulation of itch-evoked scratching in the brain remains elusive. Here, by combining fiber photometry, extracellular recording, and optogenetic manipulation, we show that the dopaminergic neurons in the ventral tegmental area play a modulatory role in itch-evoked scratching behavior. These results reveal a potential target for suppressing excessive scratching responses in patients with chronic itch.


Assuntos
Potenciais de Ação/fisiologia , Neurônios Dopaminérgicos/fisiologia , Prurido/fisiopatologia , Área Tegmentar Ventral/fisiologia , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/fisiologia , Neurônios Dopaminérgicos/química , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos , Técnicas de Cultura de Órgãos , Prurido/genética , Prurido/patologia , Área Tegmentar Ventral/química
8.
J Neurosci ; 38(36): 7833-7843, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30082422

RESUMO

Sphingosine 1-phosphate (S1P) is a bioactive signaling lipid associated with a variety of chronic pain and itch disorders. S1P signaling has been linked to cutaneous pain, but its role in itch has not yet been studied. Here, we find that S1P triggers itch and pain in male mice in a concentration-dependent manner, with low levels triggering acute itch alone and high levels triggering both pain and itch. Ca2+ imaging and electrophysiological experiments revealed that S1P signals via S1P receptor 3 (S1PR3) and TRPA1 in a subset of pruriceptors and via S1PR3 and TRPV1 in a subset of heat nociceptors. Consistent with these findings, S1P-evoked itch behaviors are selectively lost in mice lacking TRPA1, whereas S1P-evoked acute pain and heat hypersensitivity are selectively lost in mice lacking TRPV1. We conclude that S1P acts via different cellular and molecular mechanisms to trigger itch and pain. Our discovery elucidates the diverse roles that S1P signaling plays in somatosensation and provides insight into how itch and pain are discriminated in the periphery.SIGNIFICANCE STATEMENT Itch and pain are major health problems with few effective treatments. Here, we show that the proinflammatory lipid sphingosine 1-phosphate (S1P) and its receptor, S1P receptor 3 (S1PR3), trigger itch and pain behaviors via distinct molecular and cellular mechanisms. Our results provide a detailed understanding of the roles that S1P and S1PR3 play in somatosensation, highlighting their potential as targets for analgesics and antipruritics, and provide new insight into the mechanistic underpinnings of itch versus pain discrimination in the periphery.


Assuntos
Lisofosfolipídeos/metabolismo , Dor/metabolismo , Prurido/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Canais de Cátion TRPV/metabolismo , Animais , Cálcio/metabolismo , Camundongos , Camundongos Knockout , Dor/genética , Prurido/genética , Receptores de Lisoesfingolipídeo/genética , Esfingosina/metabolismo , Canais de Cátion TRPV/genética
9.
Curr Med Sci ; 38(4): 679-683, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128878

RESUMO

The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation (BDL) in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOGOOOOOO19607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOGOOOOOO 19607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.


Assuntos
Colestase/complicações , Prurido/genética , Medula Espinal/metabolismo , Transcriptoma , Animais , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prurido/etiologia , Prurido/metabolismo
10.
Sci Rep ; 8(1): 11328, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054511

RESUMO

Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in anti-inflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel.


Assuntos
Alcaloides/administração & dosagem , Antipruriginosos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Prurido/tratamento farmacológico , Quinolizinas/administração & dosagem , Alcaloides/química , Animais , Antipruriginosos/química , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Canais de Cálcio Tipo N/genética , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos , Prurido/genética , Prurido/patologia , Quinolizinas/química , Sophora/química , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
11.
Science ; 360(6388): 530-533, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29724954

RESUMO

The somatosensory system relays many signals ranging from light touch to pain and itch. Touch is critical to spatial awareness and communication. However, in disease states, innocuous mechanical stimuli can provoke pathologic sensations such as mechanical itch (alloknesis). The molecular and cellular mechanisms that govern this conversion remain unknown. We found that in mice, alloknesis in aging and dry skin is associated with a loss of Merkel cells, the touch receptors in the skin. Targeted genetic deletion of Merkel cells and associated mechanosensitive Piezo2 channels in the skin was sufficient to produce alloknesis. Chemogenetic activation of Merkel cells protected against alloknesis in dry skin. This study reveals a previously unknown function of the cutaneous touch receptors and may provide insight into the development of alloknesis.


Assuntos
Canais Iônicos/fisiologia , Mecanotransdução Celular/fisiologia , Células de Merkel/fisiologia , Prurido/fisiopatologia , Pele/inervação , Tato , Animais , Deleção de Genes , Canais Iônicos/genética , Mecanotransdução Celular/genética , Células de Merkel/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Prurido/genética
12.
Neuron ; 98(3): 482-494, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29723501

RESUMO

Itch is a unique sensory experience that is encoded by genetically distinguishable neurons both in the peripheral nervous system (PNS) and central nervous system (CNS) to elicit a characteristic behavioral response (scratching). Itch interacts with the other sensory modalities at multiple locations, from its initiation in a particular dermatome to its transmission to the brain where it is finally perceived. In this review, we summarize the current understanding of the molecular and neural mechanisms of itch by starting in the periphery, where itch is initiated, and discussing the circuits involved in itch processing in the CNS.


Assuntos
Sistema Nervoso Periférico/fisiopatologia , Prurido/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Pele/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Humanos , Sistema Nervoso Periférico/metabolismo , Prurido/genética , Prurido/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Pele/metabolismo , Pele/patologia , Medula Espinal/metabolismo
14.
J Invest Dermatol ; 138(11): 2405-2411, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29803641

RESUMO

Itch is a somatosensory modality that serves to alert an organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch, whereas chemical itch was unaffected. We examined the effect of activating the NPY/Y1 receptor system on scratch behavior in mice. We found that intrathecal administration of the Y1 agonist [Leu31,Pro34]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck compared with saline treatment, indicating that activation of the spinal NPY/Y1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y1 antagonist BIBO3304. Intrathecal application of the native nonselective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y1 system dampens both mechanically and chemically induced scratching and hence is shared by the two submodalities of itch.


Assuntos
Neuropeptídeo Y/genética , Prurido/genética , Animais , Arginina/administração & dosagem , Arginina/análogos & derivados , Modelos Animais de Doenças , Histamina/metabolismo , Humanos , Injeções Espinhais , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Mutação/genética , Neuropeptídeo Y/agonistas , Neuropeptídeo Y/metabolismo , Prurido/induzido quimicamente
15.
Elife ; 72018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29561265

RESUMO

Little is known about the capacity of lower vertebrates to experience itch. A screen of itch-inducing compounds (pruritogens) in zebrafish larvae yielded a single pruritogen, the TLR7 agonist imiquimod, that elicited a somatosensory neuron response. Imiquimod induced itch-like behaviors in zebrafish distinct from those induced by the noxious TRPA1 agonist, allyl isothiocyanate. In the zebrafish, imiquimod-evoked somatosensory neuronal responses and behaviors were entirely dependent upon TRPA1, while in the mouse TRPA1 was required for the direct activation of somatosensory neurons and partially responsible for behaviors elicited by this pruritogen. Imiquimod was found to be a direct but weak TRPA1 agonist that activated a subset of TRPA1 expressing neurons. Imiquimod-responsive TRPA1 expressing neurons were significantly more sensitive to noxious stimuli than other TRPA1 expressing neurons. Together, these results suggest a model for selective itch via activation of a specialized subpopulation of somatosensory neurons with a heightened sensitivity to noxious stimuli.


Assuntos
Modelos Animais de Doenças , Prurido/fisiopatologia , Canal de Cátion TRPA1/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Potenciais Somatossensoriais Evocados/fisiologia , Células HEK293 , Humanos , Imiquimode/farmacologia , Isotiocianatos/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Larva/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Prurido/genética , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
16.
Taiwan J Obstet Gynecol ; 57(1): 89-94, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29458911

RESUMO

OBJECTIVE: The mechanism through which neuroaxial morphine causes pruritus has not been elucidated clearly and thoroughly. MATERIALS AND METHODS: a study in 129 female parturients was conducted to investigate the effect of 14 single nucleotide polymorphisms (SNPs) on phenotype (pruritus) induced by neuroaxial (including intrathecal or epidural) morphine for cesarean section. Clinical phenotype, subjective complaints and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further. RESULTS: no significant association with the presence of phenotype (pruritus) versus genotype was observed (all p-values > 0.05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703. There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). CONCLUSION: our results showed no association between SNPs of any of the genes studied with neuroaxial morphine inducing pruritus.


Assuntos
Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Prurido/genética , Analgesia Epidural/efeitos adversos , Analgésicos Opioides/administração & dosagem , Cesárea/efeitos adversos , Feminino , Genótipo , Humanos , Morfina/administração & dosagem , Manejo da Dor , Testes Farmacogenômicos/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Estudos Prospectivos , Prurido/induzido quimicamente , Taiwan
17.
Mol Pain ; 14: 1744806918762031, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29424270

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which can detect various noxious stimuli that cause pain, inflammation, hyperalgesia, and itch. TRPV1 knock-out mice show deficiency in nociception, but the in vivo effects of persistent activation of TRPV1 are not completely understood. Here, we generated TRPV1 knock-in mice with a G564S mutation. In the heterologous expression system, an electrophysiological study showed that the G564S mutation in mouse TRPV1 caused increased basal current and a leftward shift of voltage dependence. Intriguingly, using behavioral analysis, we found that knock-in mice showed a thermosensory defect, impaired inflammatory thermal pain, and capsaicin sensitivity. We also demonstrated an attenuated behavioral response to the pruritic agent histamine in the knock-in mice. Indeed, calcium imaging together with electrophysiology showed that the overactive mutant had decreased capsaicin sensitivity. Western blot analysis revealed that the G564S mutant reduced TRPV1 phosphorylation and cell membrane trafficking. Together, we have generated a mouse model with a gain-of-function mutation in Trpv1 gene and demonstrated that the pain and histamine-dependent itch sensations in these mice are impaired due to a decreased phosphorylation level and reduced membrane localization of TRPV1.


Assuntos
Mutação com Ganho de Função/genética , Dor/genética , Dor/fisiopatologia , Prurido/genética , Prurido/fisiopatologia , Sensação , Canais de Cátion TRPV/genética , Dor Aguda/complicações , Dor Aguda/genética , Dor Aguda/patologia , Dor Aguda/fisiopatologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Comportamento Animal , Cálcio/metabolismo , Capsaicina/farmacologia , Membrana Celular/metabolismo , Técnicas de Introdução de Genes , Células HEK293 , Histamina , Humanos , Hiperalgesia/complicações , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Inflamação/complicações , Inflamação/patologia , Inflamação/fisiopatologia , Espaço Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Dor/complicações , Fosforilação , Prurido/complicações , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo , Temperatura Ambiente
18.
J Invest Dermatol ; 138(6): 1311-1317, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29317264

RESUMO

To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and nonitchy, nonlesional skin biopsies from 25 patients with atopic dermatitis and 25 patients with psoriasis and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared with healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and nonitchy skin in atopic and psoriatic subjects. Overexpression of several genes, such as phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1, in itchy skin was positively correlated with itch intensity ratings in both atopic dermatitis and psoriasis. Cytokines such as IL-17A, IL-23A, and IL-31 had elevated gene transcript levels in both itchy atopic and psoriatic skin. However, expression of genes for TRP vanilloid 2, TRP ankyrin 1, protease-activated receptor 2, protease-activated receptor 4, and IL-10 was found to be increased only in pruritic atopic skin, whereas expression of genes for TRP melastatin 8, TRP vanilloid 3, phospholipase C, and IL-36α/γ was elevated only in pruritic psoriatic skin. This "itchscriptome" analysis will lead to an increased understanding of the molecular mechanisms of chronic pruritus and provide targets for itch treatment irrespective of disease state.


Assuntos
Dermatite Atópica/genética , Prurido/genética , Psoríase/genética , Transcriptoma/imunologia , Adulto , Biópsia , Doença Crônica , Dermatite Atópica/complicações , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/imunologia , Prurido/patologia , Psoríase/complicações , Psoríase/imunologia , Psoríase/patologia , Análise de Sequência de RNA , Pele/patologia
19.
J Dermatol Sci ; 89(1): 33-39, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29122406

RESUMO

BACKGROUND: Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated. OBJECTIVE: To investigate relationship between sensitive skin and AD-associated markers. METHODS: Forty-two Japanese AD patients and 10 healthy subjects (HS) were enrolled. AD patients were divided into extrinsic (EAD; high IgE levels) and intrinsic (IAD; normal IgE levels) types. We conducted 1% LAST by assessing the four distinct sensations and calculated the frequencies of sensitive skin in EAD, IAD, and HS. We also performed clinical AD-related tests, including transepidermal water loss (TEWL), visual analogue scale (VAS) of pruritus, and quality of life, and measured laboratory markers, including blood levels of IgE, CCL17/TARC, lactate dehydrogenase (LDH) and eosinophil counts, and concentration levels of serum Th1/Th2 cytokines. Filaggrin (FLG) mutations were examined in 21 patients. These values were subjected to correlation analyses with each of the four sensation elements. RESULTS: According to the standard criteria for LAST positivity, the frequencies of LAST-positive subjects were 54.8% and 10.0% in AD and HS, respectively (P=0.014). EAD patients showed a significantly (P=0.026) higher frequency of positive LAST (65.6%) than did IAD patients (20.0%). Among the four LAST sensation elements, the crawly feeling and pain scores positively correlated with VAS of pruritus, total serum IgE, mite-specific IgE, CCL17/TARC, and/or LDH. There was no association of the LAST scores with serum Th1/Th2 cytokine levels. Notably, neither TEWL nor FLG mutations correlated with LAST positivity or any sensation scores. CONCLUSIONS: The frequency of sensitive skin is higher in EAD than in IAD. Sensitive skin is associated with AD severity, but not necessarily with barrier condition.


Assuntos
Dermatite Atópica/imunologia , Pele/imunologia , Perda Insensível de Água/fisiologia , Adulto , Idoso , Biomarcadores/sangue , Citocinas/sangue , Dermatite Atópica/sangue , Dermatite Atópica/genética , Dermatite Atópica/patologia , Feminino , Humanos , Imunoglobulina E/sangue , Proteínas de Filamentos Intermediários/genética , Ácido Láctico/toxicidade , Masculino , Pessoa de Meia-Idade , Prurido/sangue , Prurido/genética , Prurido/imunologia , Prurido/patologia , Índice de Gravidade de Doença , Pele/fisiopatologia , Testes de Irritação da Pele/métodos
20.
Curr Opin Endocrinol Diabetes Obes ; 25(1): 36-41, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29120926

RESUMO

PURPOSE OF REVIEW: The current review highlights recent advances in physiological and pharmacological researches in biology of mammalian bombesin-like peptides (BLPs). RECENT FINDINGS: BLPs and their receptors were found to have regulatory roles in many biological processes in central nervous system. Two BLPs, neuromedin B and gastrin-releasing peptide (GRP), and their receptors are required for regulation of basal and induced sighing activity in rodents. This is the first study demonstrating central pathways involved in regulation of sighing activity. GRP receptor (GRPR) expressing neurons are excitatory glutamatergic interneurons located in the dorsal lamina without projections outside the spinal cord and mediate itch signals via vesicular glutamate transporter 2. Those neurons receive itch signals and make synapses with the parabrachial nucleus projecting spinal neurons to transmit itch signals to parabrachial nucleus. GRP expressing interneurons function in a proposed 'leaky gate model' to interpret the mechanism of both pain and itch transmission. In addition to recent advances of biology in nervous system, BLPs and their receptors were found to play potential regulatory roles in innate and adaptive immune responses and tissue development. SUMMARY: Several important biological roles of BLPs and their receptors in nervous system were identified. Together with researches regarding central roles of BLPs, studies revealing the regulatory roles of BLPs and their receptors in immunology and tissue development provide us with novel insights into understanding of the biology of BLPs and their receptors.


Assuntos
Fenômenos Biológicos , Peptídeo Liberador de Gastrina/fisiologia , Neurocinina B/análogos & derivados , Receptores da Bombesina/fisiologia , Animais , Bombesina/química , Bombesina/metabolismo , Peptídeo Liberador de Gastrina/química , Glucose/metabolismo , Humanos , Neurocinina B/química , Neurocinina B/fisiologia , Organogênese/genética , Percepção da Dor/fisiologia , Prurido/genética , Prurido/metabolismo
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